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Anatomophysiology of the Henle's Loop: Emphasis on the Thick Ascending Limb

Andrée‐Anne Marcoux, Laurence E. Tremblay, Samira Slimani, Marie‐Jeanne Fiola, Fabrice Mac‐Way, Ludwig Haydock, Alexandre P. Garneau, Paul Isenring

10.1002/cphy.c210021

Source: Volume 12, Issue 1, January 2022

Published online: December 2021

Full Article on Wiley Online Library



Abstract

The loop of Henle plays a variety of important physiological roles through the concerted actions of ion transport systems in both its apical and basolateral membranes. It is involved most notably in extracellular fluid volume and blood pressure regulation as well as Ca2+, Mg2+, and acid‐base homeostasis because of its ability to reclaim a large fraction of the ultrafiltered solute load. This nephron segment is also involved in urinary concentration by energizing several of the steps that are required to generate a gradient of increasing osmolality from cortex to medulla. Another important role of the loop of Henle is to sustain a process known as tubuloglomerular feedback through the presence of specialized renal tubular cells that lie next to the juxtaglomerular arterioles. This article aims at describing these physiological roles and at discussing a number of the molecular mechanisms involved. It will also report on novel findings and uncertainties regarding the realization of certain processes and on the pathophysiological consequences of perturbed salt handling by the thick ascending limb of the loop of Henle. Since its discovery 150 years ago, the loop of Henle has remained in the spotlight and is now generating further interest because of its role in the renal‐sparing effect of SGLT2 inhibitors. © 2022 American Physiological Society. Compr Physiol 12:1‐21, 2022.

Figure 1. Figure 1. Anatomy of short and long nephrons based on a sagittal kidney section. The TALH is longer in shorter nephrons than in longer nephrons but the thin limbs are much shorter. Abbreviations: IS, inner stripe; OS, outer stripe.
Figure 2. Figure 2. Cell types lining the epithelium of the loop of Henle. (A to D) Cell types in tDLH and tALH. Type I and IV cells are characterized by a flattened and elongated appearance, a low number of organelles (especially in the case of type IV cells), and short apical microvilli (also in the case of type IV cells more strikingly). Type I cells are also known to rest on a thin basement membrane and type IV cells to interdigitate. Type II cells are taller than the other cell types in the thin loop of Henle and form extensive (labyrinthine) interdigitations between each other. They are also characterized by an abundance of microvilli and mitochondria. Type III cells resemble type I cells except that they are taller and that their basolateral membrane forms more regular infoldings. (E, F) Cell types in TALH. S and R cells are characterized by an elongate appearance, large basolateral infoldings, and a high number of bulky mitochondria. S cells are also characterized by a substantial height, a relatively smooth apical surface, and a high number of cytoplasmic vesicles while R cells are characterized by a lower height than S cells and a rough, microvilli‐containing surface. Not shown in this figure, MD cells that are similar to type II cells except for exhibiting a much greater height (even greater than S cells), larger nuclei, and a higher number of microvilli.
Figure 3. Figure 3. Ion transport systems involved in NaCl reabsorption by the TALH. Are shown: (a) NKCC2A (SLC12A1A) or NKCC2F (SLC12A1F), (b) ROMK2 or ROMK3 (KCNJ1) on the apical membrane, (c) claudin 10, 16, or 19 in the tight junctions, (d) CLCNKA or CLCNKB, (e) BSND, (f) K+ channels (see list in Table 1), and (g) a Na+/K+‐ATPase on the basolateral membrane. Red arrows are used to indicate that there is net reabsorption of these solutes. Note that NKCC2, ROMK, and CLCNK all come as more than one variant along the ALH: (1) NKCC2 as three variants (NKCC2F; NKCC2A; NKCC2B) that differ in localization (F in OMIS; A in OMOS, cortex, and MD; B in periglomerular cortex and MD), (2) CLCNK as two variants (CLCNKA; CLCNKB) that also differ in localization (A in tALH; B in TALH), and (3) ROMK as two variants (ROMK2; ROMK3) that share a similar distribution. Model of ion transport. The apical step of NaCl reabsorption is mediated by NKCC2 and the basolateral step by a Na+/K+‐ATPase, CLCNKA/Barttin, and CLCNKB/Barttin. The Na+/K+‐ATPase acts as the main driving force of NaCl reabsorption by maintaining [Na] at low levels and allowing this ion to be transported passively through NKCC2. Both the Na+/K+‐ATPase and NKCC2 are provided extracellularly with a constant supply of K+ (from the presence of nearby K+ channels) to sustain their activities. A large fraction of Na+ is also reabsorbed paracellularly via claudin 10 down a favorable electrical potential (see text).
Figure 4. Figure 4. Transport of Ca2+ and Mg2+ by the TALH. Are shown: (a) a Ca2+ channel, (b) TRPM7 on the apical membrane, (c) claudin 14, 16, or 19 in the tight junction, (d) a Na+/Ca2+ exchanger (NCX1.3), (e) a Ca2+‐ATPase (PMCA1 or PMCA4B), and (f) CNNM2 on the basolateral membrane. Red arrows are used to indicate that there is net reabsorption of these solutes. Model of ion transport. Ca2+ and Mg2+ are reabsorbed paracellularly via claudins 14, 16, and 19 down a favorable electrochemical potential (see text). A smaller fraction of Ca2+ and Mg2+ could also be reabsorbed transcellularly through channels on the apical side and additional ion transport systems on the basolateral side. Note that the role of CNNM2 as an actual Mg2+ transporter is still the subject of debate even though this protein has been linked to a hereditary form of renal Mg2+ wasting disorder.
Figure 5. Figure 5. Transport of HCO3− by the TALH. Are shown: (a) a Na+/H+ exchanger (NHE2 or NHE3) on the apical membrane and (b) a K+‐HCO3− cotransporter, (c) a Cl−/HCO3− exchanger (AE1 or AE2), and (d) a Na+‐HCO3− cotransporter (NBCn1) on the basolateral membrane. Are also shown, different CAs including, (e) GPI‐anchored CAIV and (f) GPI‐anchored CAXIV on the apical membrane, (e) GPI‐anchored CAIV and (g) GPI‐anchored CAXII on the basolateral membrane, and (h) cytosolic CAII in the cytosol. As shown in Table 1, some investigators have also identified a Cl−/HCO3− exchanger on the apical membrane (AE1) and a Na+/H+ exchanger on the basolateral membrane (NHE1 or NHE4). Model of ion transport. A fraction of the HCO3− ions that is not reclaimed by the proximal tubule is recycled by the TALH. While this process is ensured on the apical side by Na+/H+ exchangers through which H+ ions are secreted and buffered by HCO3− in the lumen, the resulting decrease in intracellular H+ concentration promotes the intracellular production of HCO3− with the assistance of CAs. HCO3− recycling is completed on the basolateral side through Cl−/HCO3− exchangers and facilitated by the presence of nearby extrusion mechanisms for Cl− such as KCC4 and Cl− channels (not shown). Note that the Na+‐HCO3− cotransporter present in the TALH is unlikely to contribute to this process as it contains only one transport site for either substrate.
Figure 6. Figure 6. Renal ammoniogenesis. The breakdown of one glutamine molecule by the renal proximal tubule leads to the production of two NH4+ and two HCO3−. One of these substrates (NH4+) is secreted into the lumen via a Na+/H+ exchanger (mainly NHE3) and directed afterward to the lumen of the collecting tubule in the form of NH3 while the other substrate (HCO3−) is reabsorbed into blood through the basolateral membrane. This whole process should thus lead to the production of four HCO3− for each glutamine that is broken down. However, a fraction of the filtered HCO3− should no longer be recycled through NHE3 due to the absence of available H+ sites. If this fraction fails to be reabsorbed through other transport pathways or compensatory mechanisms, the breakdown of one glutamine would then generate two HCO3−.
Figure 7. Figure 7. Regulation of ion transport in TALH cells. (A) Domains of WNK1. Phosphoacceptor residues are present in the kinase as well as autoinhibitory domains. A Cl−‐binding pocket and Mg2+‐sensitive residue site are also present in the kinase domain. (B) Putative model of NKCC2 regulation. In TALH cells, the same or a similar model probably could very well apply to many other ion transport systems given that the signaling intermediates or factors at play can act on many targets. As explained in the main text, UMOD has also been shown to play a role in ion transport by the TALH (not shown in the figure). Abbreviations: CaBP39, calcium‐binding protein 39; CUL3, cullin 3, KLHL3, kelch‐like 3; OSR1, oxidative stress‐responsive kinase 1; SORLA, sorting‐protein‐related receptor with A‐type repeats; SPAK, SPS1‐related proline alanine‐rich kinase; WNK, with no lysine kinase.


Figure 1. Anatomy of short and long nephrons based on a sagittal kidney section. The TALH is longer in shorter nephrons than in longer nephrons but the thin limbs are much shorter. Abbreviations: IS, inner stripe; OS, outer stripe.


Figure 2. Cell types lining the epithelium of the loop of Henle. (A to D) Cell types in tDLH and tALH. Type I and IV cells are characterized by a flattened and elongated appearance, a low number of organelles (especially in the case of type IV cells), and short apical microvilli (also in the case of type IV cells more strikingly). Type I cells are also known to rest on a thin basement membrane and type IV cells to interdigitate. Type II cells are taller than the other cell types in the thin loop of Henle and form extensive (labyrinthine) interdigitations between each other. They are also characterized by an abundance of microvilli and mitochondria. Type III cells resemble type I cells except that they are taller and that their basolateral membrane forms more regular infoldings. (E, F) Cell types in TALH. S and R cells are characterized by an elongate appearance, large basolateral infoldings, and a high number of bulky mitochondria. S cells are also characterized by a substantial height, a relatively smooth apical surface, and a high number of cytoplasmic vesicles while R cells are characterized by a lower height than S cells and a rough, microvilli‐containing surface. Not shown in this figure, MD cells that are similar to type II cells except for exhibiting a much greater height (even greater than S cells), larger nuclei, and a higher number of microvilli.


Figure 3. Ion transport systems involved in NaCl reabsorption by the TALH. Are shown: (a) NKCC2A (SLC12A1A) or NKCC2F (SLC12A1F), (b) ROMK2 or ROMK3 (KCNJ1) on the apical membrane, (c) claudin 10, 16, or 19 in the tight junctions, (d) CLCNKA or CLCNKB, (e) BSND, (f) K+ channels (see list in Table 1), and (g) a Na+/K+‐ATPase on the basolateral membrane. Red arrows are used to indicate that there is net reabsorption of these solutes. Note that NKCC2, ROMK, and CLCNK all come as more than one variant along the ALH: (1) NKCC2 as three variants (NKCC2F; NKCC2A; NKCC2B) that differ in localization (F in OMIS; A in OMOS, cortex, and MD; B in periglomerular cortex and MD), (2) CLCNK as two variants (CLCNKA; CLCNKB) that also differ in localization (A in tALH; B in TALH), and (3) ROMK as two variants (ROMK2; ROMK3) that share a similar distribution. Model of ion transport. The apical step of NaCl reabsorption is mediated by NKCC2 and the basolateral step by a Na+/K+‐ATPase, CLCNKA/Barttin, and CLCNKB/Barttin. The Na+/K+‐ATPase acts as the main driving force of NaCl reabsorption by maintaining [Na] at low levels and allowing this ion to be transported passively through NKCC2. Both the Na+/K+‐ATPase and NKCC2 are provided extracellularly with a constant supply of K+ (from the presence of nearby K+ channels) to sustain their activities. A large fraction of Na+ is also reabsorbed paracellularly via claudin 10 down a favorable electrical potential (see text).


Figure 4. Transport of Ca2+ and Mg2+ by the TALH. Are shown: (a) a Ca2+ channel, (b) TRPM7 on the apical membrane, (c) claudin 14, 16, or 19 in the tight junction, (d) a Na+/Ca2+ exchanger (NCX1.3), (e) a Ca2+‐ATPase (PMCA1 or PMCA4B), and (f) CNNM2 on the basolateral membrane. Red arrows are used to indicate that there is net reabsorption of these solutes. Model of ion transport. Ca2+ and Mg2+ are reabsorbed paracellularly via claudins 14, 16, and 19 down a favorable electrochemical potential (see text). A smaller fraction of Ca2+ and Mg2+ could also be reabsorbed transcellularly through channels on the apical side and additional ion transport systems on the basolateral side. Note that the role of CNNM2 as an actual Mg2+ transporter is still the subject of debate even though this protein has been linked to a hereditary form of renal Mg2+ wasting disorder.


Figure 5. Transport of HCO3− by the TALH. Are shown: (a) a Na+/H+ exchanger (NHE2 or NHE3) on the apical membrane and (b) a K+‐HCO3− cotransporter, (c) a Cl−/HCO3− exchanger (AE1 or AE2), and (d) a Na+‐HCO3− cotransporter (NBCn1) on the basolateral membrane. Are also shown, different CAs including, (e) GPI‐anchored CAIV and (f) GPI‐anchored CAXIV on the apical membrane, (e) GPI‐anchored CAIV and (g) GPI‐anchored CAXII on the basolateral membrane, and (h) cytosolic CAII in the cytosol. As shown in Table 1, some investigators have also identified a Cl−/HCO3− exchanger on the apical membrane (AE1) and a Na+/H+ exchanger on the basolateral membrane (NHE1 or NHE4). Model of ion transport. A fraction of the HCO3− ions that is not reclaimed by the proximal tubule is recycled by the TALH. While this process is ensured on the apical side by Na+/H+ exchangers through which H+ ions are secreted and buffered by HCO3− in the lumen, the resulting decrease in intracellular H+ concentration promotes the intracellular production of HCO3− with the assistance of CAs. HCO3− recycling is completed on the basolateral side through Cl−/HCO3− exchangers and facilitated by the presence of nearby extrusion mechanisms for Cl− such as KCC4 and Cl− channels (not shown). Note that the Na+‐HCO3− cotransporter present in the TALH is unlikely to contribute to this process as it contains only one transport site for either substrate.


Figure 6. Renal ammoniogenesis. The breakdown of one glutamine molecule by the renal proximal tubule leads to the production of two NH4+ and two HCO3−. One of these substrates (NH4+) is secreted into the lumen via a Na+/H+ exchanger (mainly NHE3) and directed afterward to the lumen of the collecting tubule in the form of NH3 while the other substrate (HCO3−) is reabsorbed into blood through the basolateral membrane. This whole process should thus lead to the production of four HCO3− for each glutamine that is broken down. However, a fraction of the filtered HCO3− should no longer be recycled through NHE3 due to the absence of available H+ sites. If this fraction fails to be reabsorbed through other transport pathways or compensatory mechanisms, the breakdown of one glutamine would then generate two HCO3−.


Figure 7. Regulation of ion transport in TALH cells. (A) Domains of WNK1. Phosphoacceptor residues are present in the kinase as well as autoinhibitory domains. A Cl−‐binding pocket and Mg2+‐sensitive residue site are also present in the kinase domain. (B) Putative model of NKCC2 regulation. In TALH cells, the same or a similar model probably could very well apply to many other ion transport systems given that the signaling intermediates or factors at play can act on many targets. As explained in the main text, UMOD has also been shown to play a role in ion transport by the TALH (not shown in the figure). Abbreviations: CaBP39, calcium‐binding protein 39; CUL3, cullin 3, KLHL3, kelch‐like 3; OSR1, oxidative stress‐responsive kinase 1; SORLA, sorting‐protein‐related receptor with A‐type repeats; SPAK, SPS1‐related proline alanine‐rich kinase; WNK, with no lysine kinase.
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Article Title: Anatomophysiology of the Henle's Loop: Emphasis on the Thick Ascending Limb
 

How to Cite

Andrée‐Anne Marcoux, Laurence E. Tremblay, Samira Slimani, Marie‐Jeanne Fiola, Fabrice Mac‐Way, Ludwig Haydock, Alexandre P. Garneau, Paul Isenring. Anatomophysiology of the Henle's Loop: Emphasis on the Thick Ascending Limb. Compr Physiol 2021, 12: 3119-3139. doi: 10.1002/cphy.c210021