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Renal Tubular Handling of Glucose and Fructose in Health and Disease

Volker Vallon, Takahiko Nakagawa

10.1002/cphy.c210030

Source: Volume 12, Issue 1, January 2022

Published online: December 2021

Full Article on Wiley Online Library



Abstract

The proximal tubule of the kidney is programmed to reabsorb all filtered glucose and fructose. Glucose is taken up by apical sodium‐glucose cotransporters SGLT2 and SGLT1 whereas SGLT5 and potentially SGLT4 and GLUT5 have been implicated in apical fructose uptake. The glucose taken up by the proximal tubule is typically not metabolized but leaves via the basolateral facilitative glucose transporter GLUT2 and is returned to the systemic circulation or used as an energy source by distal tubular segments after basolateral uptake via GLUT1. The proximal tubule generates new glucose in metabolic acidosis and the postabsorptive phase, and fructose serves as an important substrate. In fact, under physiological conditions and intake, fructose taken up by proximal tubules is primarily utilized for gluconeogenesis. In the diabetic kidney, glucose is retained and gluconeogenesis enhanced, the latter in part driven by fructose. This is maladaptive as it sustains hyperglycemia. Moreover, renal glucose retention is coupled to sodium retention through SGLT2 and SGLT1, which induces secondary deleterious effects. SGLT2 inhibitors are new anti‐hyperglycemic drugs that can protect the kidneys and heart from failing independent of kidney function and diabetes. Dietary excess of fructose also induces tubular injury. This can be magnified by kidney formation of fructose under pathological conditions. Fructose metabolism is linked to urate formation, which partially accounts for fructose‐induced tubular injury, inflammation, and hemodynamic alterations. Fructose metabolism favors glycolysis over mitochondrial respiration as urate suppresses aconitase in the tricarboxylic acid cycle, and has been linked to potentially detrimental aerobic glycolysis (Warburg effect). © 2022 American Physiological Society. Compr Physiol 12:2995‐3044, 2022.

Figure 1. Figure 1. Glucose reabsorption in the kidney. (A) Under normoglycemia, SGLT2 in the early proximal tubule reabsorbs approximately 97% of filtered glucose. The remaining approximately 3% of glucose is reabsorbed by SGLT1 in the late proximal tubule, such that urine is nearly free of glucose. SGLT2 inhibition shifts glucose reabsorption downstream and unmasks the glucose reabsorption capacity of SGLT1 (≈40% of filtered glucose, depending on glucose load; see numbers in parentheses). (B) Cell model of glucose transport: The basolateral Na+‐K+‐ATPase lowers cytosolic Na+ concentrations and generates a negative interior voltage, thereby providing the driving force for Na+‐coupled glucose uptake through SGLT2 and SGLT1 across the apical membrane. The facilitative glucose transporter GLUT2 mediates glucose transport across the basolateral membrane down its chemical gradient. Basolateral GLUT1 may contribute to reabsorb glucose or take glucose up from peritubular space. Na+‐glucose cotransport is electrogenic and accompanied by paracellular Cl− reabsorption or transcellular K+ secretion to stabilize membrane potential; K+ channels KCNE1/unknown α subunit and KCNE1/KCNQ1 in early and late proximal tubule, respectively. Modified, with permission, from Vallon V, 2011 391.
Figure 2. Figure 2. Tubular glucose reabsorption can be saturated. Tubular reabsorption of glucose increases linearly with the filtered glucose load up to the point when reabsorption reaches its maximum (Tmax glucose) and glucose starts to appear in urine. Theoretically in humans, a Tmax of approximately 350 mg/min and normal GFR would result in a plasma glucose threshold of approximately 280 mg/dL. The Tmax, however, varies between individual nephrons and, therefore, low‐level spilling of glucose into the urine initiates at modestly elevated plasma glucose levels of approximately 180 to 200 mg/dL in a healthy adult (see “Splay”). Normoglycemia is defined as fasted plasma glucose levels <100 mg/dL (<5.5 mM). SGLT2 inhibition reduces the renal glucose reabsorption to the transport capacity of SGLT1, that is, it reduces the renal glucose threshold (≈55–65 mg/dL) and Tmax (≈70 mg/min). Modified, with permission, from Vallon V, 2020 389.
Figure 3. Figure 3. Defining the contribution of SGLT2 and SGLT1 to renal glucose reabsorption. (A) Left two panels: free‐flow collections of tubular fluid were performed by micropuncture to establish a profile for fractional reabsorption of glucose versus fractional reabsorption of fluid along accessible proximal tubules at the kidney surface. Glucose reabsorption is prevented in the early proximal tubule in mice lacking SGLT2 (Sglt2−/−), but enhanced in the later proximal tubule, suggesting compensation by SGLT1. Right panel: In renal inulin clearance studies, the reduction in fractional renal glucose reabsorption in Sglt2−/− mice correlated with the amount of filtered glucose. (B) In metabolic cage studies, the SGLT2 inhibitor empagliflozin dose‐dependently increased glucose excretion in WT mice. The response curve was shifted leftward and the maximum response doubled in Sglt1−/− mice. The difference between the 2 dose‐response curves reflects glucose reabsorption via SGLT1 in WT mice. Glucosuria is initiated in WT mice when SGLT1‐mediated glucose uptake is maximal (red arrow). The difference between curves was maintained for all higher doses (same length of vertical green lines), indicating selectivity of the drug for SGLT2 versus SGLT1 in this dose range. (C) Using genetic knockout models and pharmacologic tools in renal inulin clearance studies indicated that the glucose reabsorption preserved during SGLT2 knockout or inhibition (≈40%) is mediated by SGLT1. The SGLT2 inhibitor empagliflozin was applied at low and high doses to establish free plasma concentrations (similar to concentrations in glomerular filtrate) close to IC50 for mouse SGLT2 (≈1–2 nM) or 10‐fold higher. Reused, with permission, from Rieg T, et al., 2014 313; Vallon V, et al., 2011 403.
Figure 4. Figure 4. Glucose and fructose metabolism. Most of the filtered glucose is taken up by SGLT2 in the S1 segment of the proximal tubule and leaves via basolateral GLUT2 (not shown). This is because the glycolytic potential is rather low in proximal tubules compared with further distal parts of the nephron and collecting duct system. In accordance, hexokinase (HK), the gateway enzyme of glucose metabolism that phosphorylates glucose to glucose‐6‐phosphate (Glc6P), is less active in proximal tubules relative to the rest of nephron and collecting duct. Within the proximal tubule, the highest expression and activity of HK (I, II) is in S2/S3 segments. Other key enzymes of glycolysis include phosphofructokinase (PFK) and pyruvate kinase (PKM). In contrast to glucose, fructose, which is primarily taken up by SGLT5 in S2/S3 segments, is readily phosphorylated by fructokinase (known as ketohexokinase, KHK) to produce fructose 1‐phosphate (Fru1P). Fru1P is subsequently cleaved by aldolase B (AldoB) into dihydroxyacetone phosphate (DHAP) and glyceraldehyde (GA). DHAP and GA feed into gluconeogenesis via fructose 1,6‐biphosphate (Fru1,6BP) or into glycolysis via glyceraldehyde‐3‐phosphate (G3P). G3P enters the glycolytic pathway distal to PFK and the formation of Fru1,6BP. While PFK is the most heavily regulated enzyme and is considered as the gating step of glycolysis, fructose metabolism bypasses this enzyme and lacks a negative regulatory step. In parallel, fructokinase activation sequesters a phosphate, so that intracellular phosphate and ATP levels are transiently reduced. The rapid reduction of phosphate consequently activates AMP deaminase (AMPD), which cleaves AMP to IMP. The decline in phosphate levels is attenuated by the relatively slower metabolism of Fru1P by AldoB. The latter is slowed down further by the increase in IMP, which inhibits AldoB. IMP metabolism drives urate formation. Fructose metabolism is linked to the pentose phosphate pathway (PPP) to generate nucleotides and amino acids, but also to lipid generation like triglycerides and cholesterol, and to lactate formation as an alternative energy form. Urate suppresses aconitase in TCA cycle, thereby favoring glycolysis over mitochondrial oxidative phosphorylation (OXPHOS), similar to Warburg effect. For gluconeogenesis, DHAP, G3P, and Fru1,6BP are metabolized toward glucose (red arrows). TK, triose kinase.
Figure 5. Figure 5. Coordination of glucose transport and gluconeogenesis in the proximal tubule. (1) Insulin is a physiological stimulator of SGLT2, which may serve to maximize renal glucose reabsorption capacity in situations of increased blood glucose levels, for example, following a meal. (2) At the same time, enhanced Na+‐glucose uptake and insulin suppress renal gluconeogenesis. (3) The latter, in contrast, is stimulated in the postabsorptive phase (fasting) by increased catecholamine and reduced insulin levels and involves primarily lactate as a precursor. (4) The newly formed glucose is delivered to the systemic circulation by basolateral GLUT2. (5) In metabolic acidosis, the increase in gluconeogenesis from glutamine is linked to the formation of (i) ammonium (NH4+), a renally excreted acid equivalent, and (ii) new bicarbonate, which is taken up into the circulation. The Na+‐H+‐exchanger NHE3 contributes to apical H+/NH4+ secretion and Na+/bicarbonate reabsorption. (6) The newly formed glucose can be used as fuel for proximal tubule H+ secretion or, after intercellular transfer, for intercalated cell H+ secretion. (7) SGLT2 and NHE3 are both stimulated by insulin to enhance Na+ and glucose reabsorption and their functions may be positively linked through the scaffolding protein MAP17. ?, indicates pathways that need further confirmation. Modified, with permission, from Vallon V, 2020 389.
Figure 6. Figure 6. Fructose from either diet or endogenous production can be utilized for survival. Fructose is natural fruits that stimulates fat accumulation, thereby contributing to the storage of energy that can be used when a lack of food is encountered. The freshwater Pacu fish actively feast on ripe fruits fallen into the river and become fat in the rainy season. Long‐distance migrating birds eat fruits prior to their migration to increase their fat stores. Hibernating mammals, such as bears and the ground squirrel, actively eat natural fruits to accumulate fat as an internal storage of energy for next winter season. Fresh fruits were the main dietary staple for early primates during the evolution of mankind. Moreover, pregnant women and other female mammals have the ability to produce endogenous fructose in the placenta, where fructose is used for fetal organ development during pregnancy. Naked mole rats can produce fructose endogenously in several organs for their survival under hypoxic condition. Adapted, with permission, from Johnson RJ, et al., 2019 161; Junk WJ, 1985 163.
Figure 7. Figure 7. Fructose transporters and metabolism in proximal tubular cells. There are several fructose transporters located at the apical membrane of proximal tubular epithelial cells, primarily in S2/S3 segments, including SGLT4/5 and GLUT5 as observed in rodents and humans. The rat sodium‐dependent glucose transporter‐1 (rNaGLT1) has been localized to the convoluted and the straight portions of proximal tubules in rats. In turn, GLUT2 is a facilitative transporter for fructose and glucose exit across the basolateral membrane. The proximal tubular cells are equipped with several enzymes for fructose metabolism, including fructokinase/ketohexokinase (FK/KHK), aldolase B (AldoB), and fructose 1,6 bisphosphatase (FBPase). Under fasting condition, a low level of fructose 2,6 biphosphate (Fru2,6BP) favors metabolism by FBPase over phosphofructokinase‐1 (PFK‐1) thereby metabolizing fructose 1,6 biphosphate (Fru1,6BP) toward gluconeogenesis. In turn, under satiation, a high level of Fru2,6BP activates PFK‐1 and promotes glycolysis. DHAP, dihydroxyacetone phosphate; G3P; glyceraldehyde 3‐phosphate; G6Pase, glucose 6‐phosphatase; GA, glyceraldehyde; HK, hexokinase; TK, triose kinase. Adapted, with permission, from Grempler R, et al., 2012 123; Fukuzawa T, et al., 2013.
Figure 8. Figure 8. Fructosuria in mice lacking Sglt5. (A) Plasma fructose concentrations measured under anesthesia after 3 h of fasting. Open circles represent individual mice. (B and C) Wild‐type (WT) mice and Sglt5‐deficient mice (Sglt5−/−) given plain water or 30% fructose water were maintained in metabolic cages and 24‐h urine samples collected. Despite similar plasma fructose concentrations, absolute urinary fructose excretion is significantly greater in Sglt5−/− vs WT mice given plain water, and the difference is further enhanced when given fructose water. Data are presented as means ± S.E.M (n = 8–10/group). +++, P < 0.001 versus WT mice given plain water. ***, P < 0.001 versus WT mice given fructose water. ## and ###, P < 0.01 and P < 0.001 versus respective plain water controls. Adapted, with permission, from Fukuzawa T, et al., 2013 95.
Figure 9. Figure 9. Cellular processes in the early proximal tubule linked to SGLT2 and its inhibition. Hyperglycemia enhances filtered glucose and, via SGLT2, the reabsorption of glucose and Na+ (1). Diabetes can increase SGLT2 expression (2); proposed mechanisms include tubular growth, Ang II, and HNF‐1α, which may respond to basolateral hyperglycemia sensed by GLUT2. Hyperinsulinemia and tubular growth upregulate proximal tubular transport systems, including SGLT2, NHE3, URAT1, and Na‐K‐ATPase (3). The apical transporters may be functionally coupled via scaffolding proteins, such as MAP17 (4). The resulting proximal tubular Na+ retention enhances the GFR via tubuloglomerular feedback, which by increasing brush border torque can further increase transporter density in the luminal membrane. The increase in intracellular glucose may lower SGLT2 expression via negative feedback (5). Diabetes, in part due to the associated acidosis, can enhance gluconeogenesis (6). Gluconeogenesis can be inhibited by tubular injury, hyperinsulinemia, and enhanced glucose uptake via SGLT2 (6). HNF‐1α and HNF‐3β upregulate GLUT2 (7) and thereby the basolateral exit of glucose and maintains hyperglycemia (8). Excessive SGLT2‐mediated glucose uptake may trigger apical translocation of GLUT2 (9). Hypoxia due to diabetes‐induced hyperreabsorption or kidney injury may induce HIF1α, which enhances basolateral glucose uptake via GLUT1, induces a metabolic shift to glycolysis and inhibits apical transport (10). Induction of TGF‐β1 and tubular growth may be particularly sensitive to basolateral glucose uptake via GLUT1 (11). Excessive intracellular glucose may also stimulate mTORC1 and attenuate autophagy (12). TGF‐β1 enhances cyclin‐dependent kinase inhibitors p21 and p27 and together with mTORC1 activation promotes tubular senescence, which is linked to inflammation and fibrosis. SGLT2 inhibition attenuates these deleterious effects linked to excessive intracellular glucose and hyperreabsorption. SGLT2 inhibition can also enhance gluconeogenesis, in part by lowering hyperinsulinemia. Gluconeogenesis enhances removal of intermediates from TCA cycle (cataplerosis) thereby facilitating the feeding of fatty acids and ketone bodies into the TCA cycle (anaplerosis), and enhancing oxidative phosphorylation (OxPhos) and ATP generation (13). This is associated with enhanced kidney delivery of fatty acids and ketone bodies in response to SGLT2 inhibition. Abbreviations: Ang II, angiotensin II; GFR, glomerular filtration rate; GLUT, facilitative glucose transporter; HIF‐1α, hypoxia‐inducible factor 1 alpha; HNF, hepatic nuclear factor; MAP17, 17‐kDa membrane‐associated protein; NHE3, Na‐H‐exchanger 3; OA, organic anion; TGF‐β1, transforming growth factor β1; URAT1, urate transporter 1. ?, indicates pathways that need further confirmation. Adapted, with permission, from Vallon V, 2020 389.
Figure 10. Figure 10. Basic differences in glucose versus fructose metabolism. Glucose metabolism in the kidney primarily occurs downstream of the proximal tubule and is determined by oxygen levels. (A) In the presence of sufficient oxygen (indicated by black arrow), glycolysis links to mitochondrial respiration/oxidative phosphorylation (OXPHOS) to efficiently produce high amounts of ATP. However, under low oxygen conditions (indicated by red arrow), mitochondrial respiration is disconnected from glycolysis, and lactate is produced. (B) In comparison, basic fructose metabolism is associated with glycolysis rather than mitochondrial respiration under either normoxia or hypoxia (indicated by blue arrow). A potential mechanism is that urate, a by product of fructose metabolism, suppresses aconitase (Aco), which converts citrate into iso‐citrate as part of the TCA cycle, and disconnects fructose metabolism from mitochondrial respiration.
Figure 11. Figure 11. A proposed deleterious role for SGLT1‐mediated reabsorption during recovery from ischemia‐reperfusion (IR)‐induced acute kidney injury. IR initially suppresses SGLT2 and SGLT1‐mediated reabsorption in the early and later proximal tubule, respectively, which is associated with glucosuria. Early recovery of SGLT1 expression and SGLT1‐mediated sodium reabsorption in late proximal tubule/outer medulla sustain IR‐induced hypoxia. This sustains cell injury in the outer medulla and the inhibition of NKCC2‐mediated NaCl reabsorption in the TAL, which impairs urine concentration and enhances Na‐Cl‐K delivery to macula densa ([Na‐Cl‐K]MD). The latter reduces renin expression and lowers GFR via tubuloglomerular feedback. The reduction in GFR enhances plasma creatinine and urea, the latter contributing to enhanced plasma osmolality. The sustained hypoxia and cell injury further enhance mitochondrial dysfunction, inflammation, and fibrosis, which can spread to the cortex and further suppress tubular function. Sustained suppression of SGLT2 maintains a high glucose load to downstream SGLT1, which may enhance the detrimental influence of SGLT1. Modified, with permission, from Nespoux J, et al., 2019 267.
Figure 12. Figure 12. Tubuloglomerular feedback, SGLT2 inhibition, and SGLT1 as a glucose sensor in the macula densa. (A) and (B) The tubuloglomerular feedback (TGF) establishes an inverse relationship between the delivery and concentration of Na‐Cl‐K at the macula densa and the single nephron GFR (SNGFR) of the same nephron. The operating point typically resides in the steepest part of the curve. In the diabetic kidney, a primary increase in proximal tubular reabsorption lowers Na‐Cl‐K delivery to the macula densa, which increases SNGFR through the physiology of TGF. SGLT2 inhibition attenuates proximal tubular reabsorption and increases Na‐Cl‐K delivery to the macula densa and lowers SNGFR through TGF. (C) (1 + 2) The macula densa senses an increase in luminal Na‐Cl‐K delivery by a NKCC2‐dependent mechanism, which then enhances the basolateral release of ATP. (3) ATP is converted by endonucleotidases CD73/39 to adenosine (ADO). (4) ADO activates the adenosine A1 receptor in vascular smooth muscle cells (VSMC) of the afferent arteriole to increase cytosolic Ca2+ and induce vasoconstriction and lower GFR. (5) ADO can also activate adenosine A2 receptors on VSMC of the efferent arteriole to reduce cytosolic Ca2+ and induce vasodilation. (6) Both effects contribute to the TGF mechanism and lower glomerular capillary pressure (PGC). (7) Due to upstream tubular hyperreabsorption, diabetes lowers Na‐Cl‐K delivery to the macula densa. SGLT2 inhibition attenuates the hyperreabsorption, increase Na‐Cl‐K delivery to the macula densa, and lowers GFR and PGC. (8) An increased Na‐Cl‐K delivery also activates nitric oxide synthase NOS1 in the macula densa. (9) The formed nitric oxide (NO) diffuses across the interstitium and dilates the afferent arteriole, thereby partially offsetting the afferent arteriolar vasoconstrictor tone of TGF. (10) When glucose delivery to the macula densa is increased, SGLT1 in the luminal membrane takes up glucose, a process that is linked to the phosphorylation, activation, and increased expression of NOS1 in the macula densa. The resulting enhanced NO tone dilates the afferent arteriole and enhances GFR. This can contribute to diabetes‐induced hyperfiltration, but also attenuate the reduction in GFR by SGLT2 inhibition. (11) On the other hand, SGLT2 inhibition can reduce macula densa NOS1/NO tone by inducing volume depletion. (12) ?, whether enhanced macula densa NO formation can also dilate the efferent arteriole remains to be determined. (C) Modified, with permission, from Vallon V, 2020 389.
Figure 13. Figure 13. The tubular hypothesis of diabetic glomerular hyperfiltration. (A) and (B) In vivo micropuncture studies in rats with superficial glomeruli were performed in nondiabetic and streptozotocin‐diabetic rats 404. Small amounts of blue dye were injected into Bowman space to determine nephron configuration, including the first proximal tubular loop and the early distal tubule close to the macula densa. Tubular fluid was collected close to the macula densa to determine the tubuloglomerular feedback signal ([Na‐Cl‐K]MD) and single nephron glomerular filtration rate (SNGFR; by inulin clearance). Bowman space was punctured to determine the hydrostatic pressure (PBow). Measurements were performed under control conditions and following application of the SGLT2/SGLT1 inhibitor phlorizin into the early proximal tubule, that is, without changing systemic blood glucose levels. Basal measurements (con) revealed that glomerular hyperfiltration in diabetes was associated with reductions in [Na‐Cl‐K]MD and PBow. Adding phlorizin (P) had a small effect in nondiabetic rats, but normalized [Na‐Cl‐K]MD, PBow, and SNGFR in diabetes. (C) Kidneys are programmed to retain glucose. As a consequence, diabetes induces a primary hyperreabsorption in proximal tubules involving enhanced Na+‐glucose cotransport and tubular growth. The concomitant enhanced reabsorption of sodium causes glomerular hyperfiltration through tubuloglomerular feedback ([Na‐Cl‐K]MD) and reducing tubular back pressure (PBow) thereby limiting sodium and volume retention. SGLT2 contributes to the tubular hyperreabsorption and as a consequence, SGLT2 inhibition mitigates these changes and lowers glomerular hyperfiltration. Modified, with permission, from Vallon V, and Thomson SC, 2017 410.
Figure 14. Figure 14. Proposed mechanisms of kidney protection by SGLT2 inhibition. SGLT2 inhibition counteracts the diabetes‐induced hyperreabsorption of glucose and Na+ in the early proximal tubule and lowers blood glucose levels. This also increases the NaCl and K concentration ([Na‐Cl‐K]MD) and fluid delivery (V) to the macula densa, which lowers glomerular filtration rate (GFR) through the physiology of tubuloglomerular feedback (1) and by increasing hydrostatic pressure in Bowman's space (PBow) (2). The GFR‐lowering effect of tubuloglomerular feedback includes afferent arteriole constriction (via adenosine A1 receptor) and potentially efferent arteriole dilation (via adenosine A2 receptor), which both reduce glomerular capillary pressure (PGC). Lowering of GFR reduces tubular transport work (3), thereby lowering cortical oxygen demand (QO2) (4) and increasing cortical oxygen tension (PO2) (5). Lowering GFR (6) and hyperglycemia (7) attenuates filtration of tubulo‐toxic compounds, including albumin, and reduces tubular growth and kidney inflammation. Tubular transport work is further reduced by lowering blood glucose and by cellular SGLT2 blockade itself, which reduces tubular glucotoxicity and has also been linked to inhibition of the Na‐H‐exchanger NHE3 (8). SGLT2 inhibition shifts glucose reabsorption downstream where SGLT1 compensates and reduces the risk of hypoglycemia (9). Shifting glucose and Na+ reabsorption downstream to S3 and mTAL segments increases QO2 (10) and lowers PO2 in the outer medulla (OM) (5). Furthermore, lower medullary PO2 may activate hypoxia‐inducible factor (HIF) and enhance erythropoietin (EPO) release (11). The latter increases hematocrit (Hct) (12) and improves O2 delivery to kidney medulla and cortex (13) and the heart (14). Enhanced delivery of NaCl and fluid downstream of early proximal tubule may enhance responsiveness to atrial natriuretic peptide (ANP) and diuretics (15). The diuretic, natriuretic and kaliuretic effects of SGLT2 inhibition lower the risk of hyperkalemia and further increase Hct (16) and reduce extracellular (ECV) and interstitial (ISV) volume and blood pressure (17). These effects, which are also evident by compensatory upregulation of renin and vasopressin levels (18), can help protect the failing kidney and heart (19). The increased cortical oxygen availability together with lesser hyperglycemia, tubular glucotoxicity, filtered albumin, and tubulointerstitial inflammation improves the integrity of the tubular and endothelial system, thereby allowing to maintain a higher tubular transport capacity and GFR in the long term (20). The glucosuric effect lowers therapeutic and/or endogenous insulin levels and increases glucagon concentrations (21). This induces compensatory lipolysis and hepatic gluconeogenesis and ketogenesis. SGLT2 inhibitors are uricosuric, potentially involving urate transporter 1 (URAT1) inhibition and their glucosuric and insulin‐lowering effect (22). These metabolic adaptations reduce urate levels, the hypoglycemia risk, and body and organ fat mass, which together with the resulting mild ketosis have the potential to further protect the kidney and heart (19, 23). The proposed effects are to a significant extend independent of hyperglycemia. Other abbreviations: NO, nitric oxide; UNaClV, urinary salt excretion; UV, urinary flow rate. Modified, with permission, from Vallon V, 2020 389.
Figure 15. Figure 15. Glomerular hemodynamic effects of SGLT2 inhibitor superimposed on a model of tubuloglomerular feedback (TGF), which incorporates effects on pre‐ and postglomerular resistances. Idealized TGF curves are shown for glomerular filtration rate (GFR) and PGC. The PGC curve lies to the right of the GFR curve owing to differences in the way that pre‐ and postglomerular resistances react across the range of inputs, as shown in the bottom portion of the figure. Within a group of nephrons, the position of operating points along the respective TGF curves will form a distribution. The figure shows the effects on GFR and PGC when identical increases in macula densa delivery are imposed by SGLT2 inhibitor for two nephrons drawn from this distribution (nephrons A and B). For nephron A, the TGF response to SGLT2 blocker included a large decrease in GFR and small decrease in PGC. For nephron B, there was a smaller decline in GFR and a larger decline in PGC. The inverse relationship between decreases in whole kidney GFR and decreases in average PGC for that animal is expected if animals with the smaller decreases in GFR yet larger decreases in PGC had more nephrons operating near the elbow of their respective TGF curves and vice versa. In other words, the effect of SGLT2 inhibition on GFR can over or underestimate effects on PGC depending on the location of the operating point. Modified, with permission, from Thomson SC, and Vallon V, 2021 375.
Figure 16. Figure 16. The integrated effects of SGLT1 in the diabetic kidney. (A) SGLT1 is expressed in the luminal membrane of the macula densa (MD) in human kidney. (B) Blue arrows indicate positive interactions. Hyperglycemia enhances filtered glucose and induces tubular growth. This increases Na+‐glucose cotransport, thereby maintaining hyperglycemia and reducing urinary Na+ and fluid excretion, with a larger contribution of SGLT2 versus SGLT1. Lesser urinary Na+ and fluid excretion increase effective circulating volume (ECV) and blood pressure (BP). Tubular hyperreabsorption lowers tubular backpressure in Bowman space (PBow) and the NaCl delivery and concentration at the MD, both increasing glomerular filtration rate (GFR) to restore urinary Na+ and fluid excretion. An increase in glucose delivery to the MD indicates saturated upstream Na+‐glucose cotransport. This is sensed by SGLT1 in the MD and, by stimulating MD nitric oxide synthase 1 (NOS1), further increases GFR to compensate for maximized Na+‐glucose cotransport. At the same time, SGLT1‐mediated glucose sensing may trigger tubular growth to enhance tubular glucose transport capacity. SGLT1 inhibition has a relatively small effect on diabetic tubular hyperreabsorption and thus induces little natriuresis and diuresis. Through inhibition of MD‐NOS1 upregulation and lowering of hyperfiltration, however, SGLT1 inhibition induces a relatively larger antinatriuretic and antidiuretic effect. As a consequence, SGLT1 inhibition can increase ECV with the resulting suppression in renin and increase in BP aim to restore renal Na+ and fluid excretion and ECV. (C) Diabetic Akita mice show enhanced MD NOS1 expression and higher GFR versus controls. Gene knockout of SGLT1 (Sglt1−/−) blunted both effects. (D) The classic TGF mechanism explains the increase in GFR when filtered glucose is increased up to the transport maximum for glucose (TM glucose). A further increase in filtered glucose can enhance MD NaCl and fluid delivery by the osmotic diuresis due to nonreabsorbed glucose, which would lower GFR. MD glucose sensing provides an additional stimulus to raise GFR and maintain hyperfiltration. EGM, extraglomerular mesangium, TALH, thick ascending limb. ?, indicate pathways that need further confirmation. Adapted, with permission, from Song P, et al., 2019 355.
Figure 17. Figure 17. Mechanisms by which excessive fructose causes kidney diseases. Under physiological conditions, fructose links to gluconeogenesis, and may protect from hypoxia and maintain systemic glucose concentrations, and preserves renal function. In turn, endogenous fructose formation is enhanced under several pathological conditions, including diabetes, ischemia, dehydration, senescence, and pressure overload. Either excessive dietary fructose or aberrant endogenous fructose generation stimulates the pathological pathway to cause tubulointerstitial damage and endothelial dysfunction in association with urate production and inflammation. Fructose metabolism links to the Warburg effect, which favors an unbalanced increase of glycolysis with suppressed mitochondrial respiration and stimulation of lactate production under aerobic conditions. These processes could be involved in the development of acute kidney injury (AKI), diabetic nephropathy, chronic kidney disease (CKD), senescence, or deleterious consequences of dehydration. Recurrent dehydration has been proposed to induce renal injury via a fructokinase‐dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Adapted, with permission, from Roncal Jimenez CA, et al., 2014 317.


Figure 1. Glucose reabsorption in the kidney. (A) Under normoglycemia, SGLT2 in the early proximal tubule reabsorbs approximately 97% of filtered glucose. The remaining approximately 3% of glucose is reabsorbed by SGLT1 in the late proximal tubule, such that urine is nearly free of glucose. SGLT2 inhibition shifts glucose reabsorption downstream and unmasks the glucose reabsorption capacity of SGLT1 (≈40% of filtered glucose, depending on glucose load; see numbers in parentheses). (B) Cell model of glucose transport: The basolateral Na+‐K+‐ATPase lowers cytosolic Na+ concentrations and generates a negative interior voltage, thereby providing the driving force for Na+‐coupled glucose uptake through SGLT2 and SGLT1 across the apical membrane. The facilitative glucose transporter GLUT2 mediates glucose transport across the basolateral membrane down its chemical gradient. Basolateral GLUT1 may contribute to reabsorb glucose or take glucose up from peritubular space. Na+‐glucose cotransport is electrogenic and accompanied by paracellular Cl− reabsorption or transcellular K+ secretion to stabilize membrane potential; K+ channels KCNE1/unknown α subunit and KCNE1/KCNQ1 in early and late proximal tubule, respectively. Modified, with permission, from Vallon V, 2011 391.


Figure 2. Tubular glucose reabsorption can be saturated. Tubular reabsorption of glucose increases linearly with the filtered glucose load up to the point when reabsorption reaches its maximum (Tmax glucose) and glucose starts to appear in urine. Theoretically in humans, a Tmax of approximately 350 mg/min and normal GFR would result in a plasma glucose threshold of approximately 280 mg/dL. The Tmax, however, varies between individual nephrons and, therefore, low‐level spilling of glucose into the urine initiates at modestly elevated plasma glucose levels of approximately 180 to 200 mg/dL in a healthy adult (see “Splay”). Normoglycemia is defined as fasted plasma glucose levels <100 mg/dL (<5.5 mM). SGLT2 inhibition reduces the renal glucose reabsorption to the transport capacity of SGLT1, that is, it reduces the renal glucose threshold (≈55–65 mg/dL) and Tmax (≈70 mg/min). Modified, with permission, from Vallon V, 2020 389.


Figure 3. Defining the contribution of SGLT2 and SGLT1 to renal glucose reabsorption. (A) Left two panels: free‐flow collections of tubular fluid were performed by micropuncture to establish a profile for fractional reabsorption of glucose versus fractional reabsorption of fluid along accessible proximal tubules at the kidney surface. Glucose reabsorption is prevented in the early proximal tubule in mice lacking SGLT2 (Sglt2−/−), but enhanced in the later proximal tubule, suggesting compensation by SGLT1. Right panel: In renal inulin clearance studies, the reduction in fractional renal glucose reabsorption in Sglt2−/− mice correlated with the amount of filtered glucose. (B) In metabolic cage studies, the SGLT2 inhibitor empagliflozin dose‐dependently increased glucose excretion in WT mice. The response curve was shifted leftward and the maximum response doubled in Sglt1−/− mice. The difference between the 2 dose‐response curves reflects glucose reabsorption via SGLT1 in WT mice. Glucosuria is initiated in WT mice when SGLT1‐mediated glucose uptake is maximal (red arrow). The difference between curves was maintained for all higher doses (same length of vertical green lines), indicating selectivity of the drug for SGLT2 versus SGLT1 in this dose range. (C) Using genetic knockout models and pharmacologic tools in renal inulin clearance studies indicated that the glucose reabsorption preserved during SGLT2 knockout or inhibition (≈40%) is mediated by SGLT1. The SGLT2 inhibitor empagliflozin was applied at low and high doses to establish free plasma concentrations (similar to concentrations in glomerular filtrate) close to IC50 for mouse SGLT2 (≈1–2 nM) or 10‐fold higher. Reused, with permission, from Rieg T, et al., 2014 313; Vallon V, et al., 2011 403.


Figure 4. Glucose and fructose metabolism. Most of the filtered glucose is taken up by SGLT2 in the S1 segment of the proximal tubule and leaves via basolateral GLUT2 (not shown). This is because the glycolytic potential is rather low in proximal tubules compared with further distal parts of the nephron and collecting duct system. In accordance, hexokinase (HK), the gateway enzyme of glucose metabolism that phosphorylates glucose to glucose‐6‐phosphate (Glc6P), is less active in proximal tubules relative to the rest of nephron and collecting duct. Within the proximal tubule, the highest expression and activity of HK (I, II) is in S2/S3 segments. Other key enzymes of glycolysis include phosphofructokinase (PFK) and pyruvate kinase (PKM). In contrast to glucose, fructose, which is primarily taken up by SGLT5 in S2/S3 segments, is readily phosphorylated by fructokinase (known as ketohexokinase, KHK) to produce fructose 1‐phosphate (Fru1P). Fru1P is subsequently cleaved by aldolase B (AldoB) into dihydroxyacetone phosphate (DHAP) and glyceraldehyde (GA). DHAP and GA feed into gluconeogenesis via fructose 1,6‐biphosphate (Fru1,6BP) or into glycolysis via glyceraldehyde‐3‐phosphate (G3P). G3P enters the glycolytic pathway distal to PFK and the formation of Fru1,6BP. While PFK is the most heavily regulated enzyme and is considered as the gating step of glycolysis, fructose metabolism bypasses this enzyme and lacks a negative regulatory step. In parallel, fructokinase activation sequesters a phosphate, so that intracellular phosphate and ATP levels are transiently reduced. The rapid reduction of phosphate consequently activates AMP deaminase (AMPD), which cleaves AMP to IMP. The decline in phosphate levels is attenuated by the relatively slower metabolism of Fru1P by AldoB. The latter is slowed down further by the increase in IMP, which inhibits AldoB. IMP metabolism drives urate formation. Fructose metabolism is linked to the pentose phosphate pathway (PPP) to generate nucleotides and amino acids, but also to lipid generation like triglycerides and cholesterol, and to lactate formation as an alternative energy form. Urate suppresses aconitase in TCA cycle, thereby favoring glycolysis over mitochondrial oxidative phosphorylation (OXPHOS), similar to Warburg effect. For gluconeogenesis, DHAP, G3P, and Fru1,6BP are metabolized toward glucose (red arrows). TK, triose kinase.


Figure 5. Coordination of glucose transport and gluconeogenesis in the proximal tubule. (1) Insulin is a physiological stimulator of SGLT2, which may serve to maximize renal glucose reabsorption capacity in situations of increased blood glucose levels, for example, following a meal. (2) At the same time, enhanced Na+‐glucose uptake and insulin suppress renal gluconeogenesis. (3) The latter, in contrast, is stimulated in the postabsorptive phase (fasting) by increased catecholamine and reduced insulin levels and involves primarily lactate as a precursor. (4) The newly formed glucose is delivered to the systemic circulation by basolateral GLUT2. (5) In metabolic acidosis, the increase in gluconeogenesis from glutamine is linked to the formation of (i) ammonium (NH4+), a renally excreted acid equivalent, and (ii) new bicarbonate, which is taken up into the circulation. The Na+‐H+‐exchanger NHE3 contributes to apical H+/NH4+ secretion and Na+/bicarbonate reabsorption. (6) The newly formed glucose can be used as fuel for proximal tubule H+ secretion or, after intercellular transfer, for intercalated cell H+ secretion. (7) SGLT2 and NHE3 are both stimulated by insulin to enhance Na+ and glucose reabsorption and their functions may be positively linked through the scaffolding protein MAP17. ?, indicates pathways that need further confirmation. Modified, with permission, from Vallon V, 2020 389.


Figure 6. Fructose from either diet or endogenous production can be utilized for survival. Fructose is natural fruits that stimulates fat accumulation, thereby contributing to the storage of energy that can be used when a lack of food is encountered. The freshwater Pacu fish actively feast on ripe fruits fallen into the river and become fat in the rainy season. Long‐distance migrating birds eat fruits prior to their migration to increase their fat stores. Hibernating mammals, such as bears and the ground squirrel, actively eat natural fruits to accumulate fat as an internal storage of energy for next winter season. Fresh fruits were the main dietary staple for early primates during the evolution of mankind. Moreover, pregnant women and other female mammals have the ability to produce endogenous fructose in the placenta, where fructose is used for fetal organ development during pregnancy. Naked mole rats can produce fructose endogenously in several organs for their survival under hypoxic condition. Adapted, with permission, from Johnson RJ, et al., 2019 161; Junk WJ, 1985 163.


Figure 7. Fructose transporters and metabolism in proximal tubular cells. There are several fructose transporters located at the apical membrane of proximal tubular epithelial cells, primarily in S2/S3 segments, including SGLT4/5 and GLUT5 as observed in rodents and humans. The rat sodium‐dependent glucose transporter‐1 (rNaGLT1) has been localized to the convoluted and the straight portions of proximal tubules in rats. In turn, GLUT2 is a facilitative transporter for fructose and glucose exit across the basolateral membrane. The proximal tubular cells are equipped with several enzymes for fructose metabolism, including fructokinase/ketohexokinase (FK/KHK), aldolase B (AldoB), and fructose 1,6 bisphosphatase (FBPase). Under fasting condition, a low level of fructose 2,6 biphosphate (Fru2,6BP) favors metabolism by FBPase over phosphofructokinase‐1 (PFK‐1) thereby metabolizing fructose 1,6 biphosphate (Fru1,6BP) toward gluconeogenesis. In turn, under satiation, a high level of Fru2,6BP activates PFK‐1 and promotes glycolysis. DHAP, dihydroxyacetone phosphate; G3P; glyceraldehyde 3‐phosphate; G6Pase, glucose 6‐phosphatase; GA, glyceraldehyde; HK, hexokinase; TK, triose kinase. Adapted, with permission, from Grempler R, et al., 2012 123; Fukuzawa T, et al., 2013.


Figure 8. Fructosuria in mice lacking Sglt5. (A) Plasma fructose concentrations measured under anesthesia after 3 h of fasting. Open circles represent individual mice. (B and C) Wild‐type (WT) mice and Sglt5‐deficient mice (Sglt5−/−) given plain water or 30% fructose water were maintained in metabolic cages and 24‐h urine samples collected. Despite similar plasma fructose concentrations, absolute urinary fructose excretion is significantly greater in Sglt5−/− vs WT mice given plain water, and the difference is further enhanced when given fructose water. Data are presented as means ± S.E.M (n = 8–10/group). +++, P < 0.001 versus WT mice given plain water. ***, P < 0.001 versus WT mice given fructose water. ## and ###, P < 0.01 and P < 0.001 versus respective plain water controls. Adapted, with permission, from Fukuzawa T, et al., 2013 95.


Figure 9. Cellular processes in the early proximal tubule linked to SGLT2 and its inhibition. Hyperglycemia enhances filtered glucose and, via SGLT2, the reabsorption of glucose and Na+ (1). Diabetes can increase SGLT2 expression (2); proposed mechanisms include tubular growth, Ang II, and HNF‐1α, which may respond to basolateral hyperglycemia sensed by GLUT2. Hyperinsulinemia and tubular growth upregulate proximal tubular transport systems, including SGLT2, NHE3, URAT1, and Na‐K‐ATPase (3). The apical transporters may be functionally coupled via scaffolding proteins, such as MAP17 (4). The resulting proximal tubular Na+ retention enhances the GFR via tubuloglomerular feedback, which by increasing brush border torque can further increase transporter density in the luminal membrane. The increase in intracellular glucose may lower SGLT2 expression via negative feedback (5). Diabetes, in part due to the associated acidosis, can enhance gluconeogenesis (6). Gluconeogenesis can be inhibited by tubular injury, hyperinsulinemia, and enhanced glucose uptake via SGLT2 (6). HNF‐1α and HNF‐3β upregulate GLUT2 (7) and thereby the basolateral exit of glucose and maintains hyperglycemia (8). Excessive SGLT2‐mediated glucose uptake may trigger apical translocation of GLUT2 (9). Hypoxia due to diabetes‐induced hyperreabsorption or kidney injury may induce HIF1α, which enhances basolateral glucose uptake via GLUT1, induces a metabolic shift to glycolysis and inhibits apical transport (10). Induction of TGF‐β1 and tubular growth may be particularly sensitive to basolateral glucose uptake via GLUT1 (11). Excessive intracellular glucose may also stimulate mTORC1 and attenuate autophagy (12). TGF‐β1 enhances cyclin‐dependent kinase inhibitors p21 and p27 and together with mTORC1 activation promotes tubular senescence, which is linked to inflammation and fibrosis. SGLT2 inhibition attenuates these deleterious effects linked to excessive intracellular glucose and hyperreabsorption. SGLT2 inhibition can also enhance gluconeogenesis, in part by lowering hyperinsulinemia. Gluconeogenesis enhances removal of intermediates from TCA cycle (cataplerosis) thereby facilitating the feeding of fatty acids and ketone bodies into the TCA cycle (anaplerosis), and enhancing oxidative phosphorylation (OxPhos) and ATP generation (13). This is associated with enhanced kidney delivery of fatty acids and ketone bodies in response to SGLT2 inhibition. Abbreviations: Ang II, angiotensin II; GFR, glomerular filtration rate; GLUT, facilitative glucose transporter; HIF‐1α, hypoxia‐inducible factor 1 alpha; HNF, hepatic nuclear factor; MAP17, 17‐kDa membrane‐associated protein; NHE3, Na‐H‐exchanger 3; OA, organic anion; TGF‐β1, transforming growth factor β1; URAT1, urate transporter 1. ?, indicates pathways that need further confirmation. Adapted, with permission, from Vallon V, 2020 389.


Figure 10. Basic differences in glucose versus fructose metabolism. Glucose metabolism in the kidney primarily occurs downstream of the proximal tubule and is determined by oxygen levels. (A) In the presence of sufficient oxygen (indicated by black arrow), glycolysis links to mitochondrial respiration/oxidative phosphorylation (OXPHOS) to efficiently produce high amounts of ATP. However, under low oxygen conditions (indicated by red arrow), mitochondrial respiration is disconnected from glycolysis, and lactate is produced. (B) In comparison, basic fructose metabolism is associated with glycolysis rather than mitochondrial respiration under either normoxia or hypoxia (indicated by blue arrow). A potential mechanism is that urate, a by product of fructose metabolism, suppresses aconitase (Aco), which converts citrate into iso‐citrate as part of the TCA cycle, and disconnects fructose metabolism from mitochondrial respiration.


Figure 11. A proposed deleterious role for SGLT1‐mediated reabsorption during recovery from ischemia‐reperfusion (IR)‐induced acute kidney injury. IR initially suppresses SGLT2 and SGLT1‐mediated reabsorption in the early and later proximal tubule, respectively, which is associated with glucosuria. Early recovery of SGLT1 expression and SGLT1‐mediated sodium reabsorption in late proximal tubule/outer medulla sustain IR‐induced hypoxia. This sustains cell injury in the outer medulla and the inhibition of NKCC2‐mediated NaCl reabsorption in the TAL, which impairs urine concentration and enhances Na‐Cl‐K delivery to macula densa ([Na‐Cl‐K]MD). The latter reduces renin expression and lowers GFR via tubuloglomerular feedback. The reduction in GFR enhances plasma creatinine and urea, the latter contributing to enhanced plasma osmolality. The sustained hypoxia and cell injury further enhance mitochondrial dysfunction, inflammation, and fibrosis, which can spread to the cortex and further suppress tubular function. Sustained suppression of SGLT2 maintains a high glucose load to downstream SGLT1, which may enhance the detrimental influence of SGLT1. Modified, with permission, from Nespoux J, et al., 2019 267.


Figure 12. Tubuloglomerular feedback, SGLT2 inhibition, and SGLT1 as a glucose sensor in the macula densa. (A) and (B) The tubuloglomerular feedback (TGF) establishes an inverse relationship between the delivery and concentration of Na‐Cl‐K at the macula densa and the single nephron GFR (SNGFR) of the same nephron. The operating point typically resides in the steepest part of the curve. In the diabetic kidney, a primary increase in proximal tubular reabsorption lowers Na‐Cl‐K delivery to the macula densa, which increases SNGFR through the physiology of TGF. SGLT2 inhibition attenuates proximal tubular reabsorption and increases Na‐Cl‐K delivery to the macula densa and lowers SNGFR through TGF. (C) (1 + 2) The macula densa senses an increase in luminal Na‐Cl‐K delivery by a NKCC2‐dependent mechanism, which then enhances the basolateral release of ATP. (3) ATP is converted by endonucleotidases CD73/39 to adenosine (ADO). (4) ADO activates the adenosine A1 receptor in vascular smooth muscle cells (VSMC) of the afferent arteriole to increase cytosolic Ca2+ and induce vasoconstriction and lower GFR. (5) ADO can also activate adenosine A2 receptors on VSMC of the efferent arteriole to reduce cytosolic Ca2+ and induce vasodilation. (6) Both effects contribute to the TGF mechanism and lower glomerular capillary pressure (PGC). (7) Due to upstream tubular hyperreabsorption, diabetes lowers Na‐Cl‐K delivery to the macula densa. SGLT2 inhibition attenuates the hyperreabsorption, increase Na‐Cl‐K delivery to the macula densa, and lowers GFR and PGC. (8) An increased Na‐Cl‐K delivery also activates nitric oxide synthase NOS1 in the macula densa. (9) The formed nitric oxide (NO) diffuses across the interstitium and dilates the afferent arteriole, thereby partially offsetting the afferent arteriolar vasoconstrictor tone of TGF. (10) When glucose delivery to the macula densa is increased, SGLT1 in the luminal membrane takes up glucose, a process that is linked to the phosphorylation, activation, and increased expression of NOS1 in the macula densa. The resulting enhanced NO tone dilates the afferent arteriole and enhances GFR. This can contribute to diabetes‐induced hyperfiltration, but also attenuate the reduction in GFR by SGLT2 inhibition. (11) On the other hand, SGLT2 inhibition can reduce macula densa NOS1/NO tone by inducing volume depletion. (12) ?, whether enhanced macula densa NO formation can also dilate the efferent arteriole remains to be determined. (C) Modified, with permission, from Vallon V, 2020 389.


Figure 13. The tubular hypothesis of diabetic glomerular hyperfiltration. (A) and (B) In vivo micropuncture studies in rats with superficial glomeruli were performed in nondiabetic and streptozotocin‐diabetic rats 404. Small amounts of blue dye were injected into Bowman space to determine nephron configuration, including the first proximal tubular loop and the early distal tubule close to the macula densa. Tubular fluid was collected close to the macula densa to determine the tubuloglomerular feedback signal ([Na‐Cl‐K]MD) and single nephron glomerular filtration rate (SNGFR; by inulin clearance). Bowman space was punctured to determine the hydrostatic pressure (PBow). Measurements were performed under control conditions and following application of the SGLT2/SGLT1 inhibitor phlorizin into the early proximal tubule, that is, without changing systemic blood glucose levels. Basal measurements (con) revealed that glomerular hyperfiltration in diabetes was associated with reductions in [Na‐Cl‐K]MD and PBow. Adding phlorizin (P) had a small effect in nondiabetic rats, but normalized [Na‐Cl‐K]MD, PBow, and SNGFR in diabetes. (C) Kidneys are programmed to retain glucose. As a consequence, diabetes induces a primary hyperreabsorption in proximal tubules involving enhanced Na+‐glucose cotransport and tubular growth. The concomitant enhanced reabsorption of sodium causes glomerular hyperfiltration through tubuloglomerular feedback ([Na‐Cl‐K]MD) and reducing tubular back pressure (PBow) thereby limiting sodium and volume retention. SGLT2 contributes to the tubular hyperreabsorption and as a consequence, SGLT2 inhibition mitigates these changes and lowers glomerular hyperfiltration. Modified, with permission, from Vallon V, and Thomson SC, 2017 410.


Figure 14. Proposed mechanisms of kidney protection by SGLT2 inhibition. SGLT2 inhibition counteracts the diabetes‐induced hyperreabsorption of glucose and Na+ in the early proximal tubule and lowers blood glucose levels. This also increases the NaCl and K concentration ([Na‐Cl‐K]MD) and fluid delivery (V) to the macula densa, which lowers glomerular filtration rate (GFR) through the physiology of tubuloglomerular feedback (1) and by increasing hydrostatic pressure in Bowman's space (PBow) (2). The GFR‐lowering effect of tubuloglomerular feedback includes afferent arteriole constriction (via adenosine A1 receptor) and potentially efferent arteriole dilation (via adenosine A2 receptor), which both reduce glomerular capillary pressure (PGC). Lowering of GFR reduces tubular transport work (3), thereby lowering cortical oxygen demand (QO2) (4) and increasing cortical oxygen tension (PO2) (5). Lowering GFR (6) and hyperglycemia (7) attenuates filtration of tubulo‐toxic compounds, including albumin, and reduces tubular growth and kidney inflammation. Tubular transport work is further reduced by lowering blood glucose and by cellular SGLT2 blockade itself, which reduces tubular glucotoxicity and has also been linked to inhibition of the Na‐H‐exchanger NHE3 (8). SGLT2 inhibition shifts glucose reabsorption downstream where SGLT1 compensates and reduces the risk of hypoglycemia (9). Shifting glucose and Na+ reabsorption downstream to S3 and mTAL segments increases QO2 (10) and lowers PO2 in the outer medulla (OM) (5). Furthermore, lower medullary PO2 may activate hypoxia‐inducible factor (HIF) and enhance erythropoietin (EPO) release (11). The latter increases hematocrit (Hct) (12) and improves O2 delivery to kidney medulla and cortex (13) and the heart (14). Enhanced delivery of NaCl and fluid downstream of early proximal tubule may enhance responsiveness to atrial natriuretic peptide (ANP) and diuretics (15). The diuretic, natriuretic and kaliuretic effects of SGLT2 inhibition lower the risk of hyperkalemia and further increase Hct (16) and reduce extracellular (ECV) and interstitial (ISV) volume and blood pressure (17). These effects, which are also evident by compensatory upregulation of renin and vasopressin levels (18), can help protect the failing kidney and heart (19). The increased cortical oxygen availability together with lesser hyperglycemia, tubular glucotoxicity, filtered albumin, and tubulointerstitial inflammation improves the integrity of the tubular and endothelial system, thereby allowing to maintain a higher tubular transport capacity and GFR in the long term (20). The glucosuric effect lowers therapeutic and/or endogenous insulin levels and increases glucagon concentrations (21). This induces compensatory lipolysis and hepatic gluconeogenesis and ketogenesis. SGLT2 inhibitors are uricosuric, potentially involving urate transporter 1 (URAT1) inhibition and their glucosuric and insulin‐lowering effect (22). These metabolic adaptations reduce urate levels, the hypoglycemia risk, and body and organ fat mass, which together with the resulting mild ketosis have the potential to further protect the kidney and heart (19, 23). The proposed effects are to a significant extend independent of hyperglycemia. Other abbreviations: NO, nitric oxide; UNaClV, urinary salt excretion; UV, urinary flow rate. Modified, with permission, from Vallon V, 2020 389.


Figure 15. Glomerular hemodynamic effects of SGLT2 inhibitor superimposed on a model of tubuloglomerular feedback (TGF), which incorporates effects on pre‐ and postglomerular resistances. Idealized TGF curves are shown for glomerular filtration rate (GFR) and PGC. The PGC curve lies to the right of the GFR curve owing to differences in the way that pre‐ and postglomerular resistances react across the range of inputs, as shown in the bottom portion of the figure. Within a group of nephrons, the position of operating points along the respective TGF curves will form a distribution. The figure shows the effects on GFR and PGC when identical increases in macula densa delivery are imposed by SGLT2 inhibitor for two nephrons drawn from this distribution (nephrons A and B). For nephron A, the TGF response to SGLT2 blocker included a large decrease in GFR and small decrease in PGC. For nephron B, there was a smaller decline in GFR and a larger decline in PGC. The inverse relationship between decreases in whole kidney GFR and decreases in average PGC for that animal is expected if animals with the smaller decreases in GFR yet larger decreases in PGC had more nephrons operating near the elbow of their respective TGF curves and vice versa. In other words, the effect of SGLT2 inhibition on GFR can over or underestimate effects on PGC depending on the location of the operating point. Modified, with permission, from Thomson SC, and Vallon V, 2021 375.


Figure 16. The integrated effects of SGLT1 in the diabetic kidney. (A) SGLT1 is expressed in the luminal membrane of the macula densa (MD) in human kidney. (B) Blue arrows indicate positive interactions. Hyperglycemia enhances filtered glucose and induces tubular growth. This increases Na+‐glucose cotransport, thereby maintaining hyperglycemia and reducing urinary Na+ and fluid excretion, with a larger contribution of SGLT2 versus SGLT1. Lesser urinary Na+ and fluid excretion increase effective circulating volume (ECV) and blood pressure (BP). Tubular hyperreabsorption lowers tubular backpressure in Bowman space (PBow) and the NaCl delivery and concentration at the MD, both increasing glomerular filtration rate (GFR) to restore urinary Na+ and fluid excretion. An increase in glucose delivery to the MD indicates saturated upstream Na+‐glucose cotransport. This is sensed by SGLT1 in the MD and, by stimulating MD nitric oxide synthase 1 (NOS1), further increases GFR to compensate for maximized Na+‐glucose cotransport. At the same time, SGLT1‐mediated glucose sensing may trigger tubular growth to enhance tubular glucose transport capacity. SGLT1 inhibition has a relatively small effect on diabetic tubular hyperreabsorption and thus induces little natriuresis and diuresis. Through inhibition of MD‐NOS1 upregulation and lowering of hyperfiltration, however, SGLT1 inhibition induces a relatively larger antinatriuretic and antidiuretic effect. As a consequence, SGLT1 inhibition can increase ECV with the resulting suppression in renin and increase in BP aim to restore renal Na+ and fluid excretion and ECV. (C) Diabetic Akita mice show enhanced MD NOS1 expression and higher GFR versus controls. Gene knockout of SGLT1 (Sglt1−/−) blunted both effects. (D) The classic TGF mechanism explains the increase in GFR when filtered glucose is increased up to the transport maximum for glucose (TM glucose). A further increase in filtered glucose can enhance MD NaCl and fluid delivery by the osmotic diuresis due to nonreabsorbed glucose, which would lower GFR. MD glucose sensing provides an additional stimulus to raise GFR and maintain hyperfiltration. EGM, extraglomerular mesangium, TALH, thick ascending limb. ?, indicate pathways that need further confirmation. Adapted, with permission, from Song P, et al., 2019 355.


Figure 17. Mechanisms by which excessive fructose causes kidney diseases. Under physiological conditions, fructose links to gluconeogenesis, and may protect from hypoxia and maintain systemic glucose concentrations, and preserves renal function. In turn, endogenous fructose formation is enhanced under several pathological conditions, including diabetes, ischemia, dehydration, senescence, and pressure overload. Either excessive dietary fructose or aberrant endogenous fructose generation stimulates the pathological pathway to cause tubulointerstitial damage and endothelial dysfunction in association with urate production and inflammation. Fructose metabolism links to the Warburg effect, which favors an unbalanced increase of glycolysis with suppressed mitochondrial respiration and stimulation of lactate production under aerobic conditions. These processes could be involved in the development of acute kidney injury (AKI), diabetic nephropathy, chronic kidney disease (CKD), senescence, or deleterious consequences of dehydration. Recurrent dehydration has been proposed to induce renal injury via a fructokinase‐dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Adapted, with permission, from Roncal Jimenez CA, et al., 2014 317.
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Article Title: Renal Tubular Handling of Glucose and Fructose in Health and Disease
 

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Volker Vallon, Takahiko Nakagawa. Renal Tubular Handling of Glucose and Fructose in Health and Disease. Compr Physiol 2021, 12: 2995-3044. doi: 10.1002/cphy.c210030