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The Role of Macula Densa Nitric Oxide Synthase 1 Beta Splice Variant in Modulating Tubuloglomerular Feedback

Ruisheng Liu, Luis A. Juncos, Yan Lu, Jin Wei, Jie Zhang, Lei Wang, En Y. Lai, Mattias Carlstrom, A. Erik G. Persson

10.1002/cphy.c210043

Source: Volume 13, Issue 1, January 2023

Published online: January 2023

Full Article on Wiley Online Library



Abstract

Abnormalities in renal electrolyte and water excretion may result in inappropriate salt and water retention, which facilitates the development and maintenance of hypertension, as well as acid‐base and electrolyte disorders. A key mechanism by which the kidney regulates renal hemodynamics and electrolyte excretion is via tubuloglomerular feedback (TGF), an intrarenal negative feedback between tubules and arterioles. TGF is initiated by an increase of NaCl delivery at the macula densa cells. The increased NaCl activates luminal Na‐K‐2Cl cotransporter (NKCC2) of the macula densa cells, which leads to activation of several intracellular processes followed by the production of paracrine signals that ultimately result in a constriction of the afferent arteriole and a tonic inhibition of single nephron glomerular filtration rate. Neuronal nitric oxide (NOS1) is highly expressed in the macula densa. NOS1β is the major splice variant and accounts for most of NO generation by the macula densa, which inhibits TGF response. Macula densa NOS1β‐mediated modulation of TGF responses plays an essential role in control of sodium excretion, volume and electrolyte hemostasis, and blood pressure. In this article, we describe the mechanisms that regulate macula densa‐derived NO and their effect on TGF response in physiologic and pathologic conditions. © 2023 American Physiological Society. Compr Physiol 13:4215‐4229, 2023.

Figure 1. Figure 1. (A) The kidney via its functional units, the nephrons, importantly contribute to maintain body fluid and electrolyte homeostasis. Tubuloglomerular feedback (TGF) is operating within the juxtaglomerular apparatus (JGA), which consists of specialized structures/cells in the region between the thick ascending limb (TAL) of the loop of Henle and the distal convoluted tubule, near the afferent arteriole. TGF is initiated via mechanisms located to the macula densa sense and reacts in response to changes in tubular lumen NaCl. At high NaCl load, a paracrine signal is generated and transferred from macula densa in the TAL to the adjacent endothelial and vascular smooth muscle cells of the afferent arteriole. Tuning of the TGF is modulated by the activity of the enzyme isoforms nitric oxide synthase 1 (NOS1) and NAD(P)H oxidase 2 (NOX). The former enzyme exists in three different splice variants, that is alpha (α), beta (β), and gamma (γ), which all are known to generate nitric oxide (NO). Bioavailability and signaling of NOS1‐derived NO are dampened, via scavenging, by NOX2‐derived reactive oxygen species (ROS) including superoxide (O2−). Conditions with oxidative stress (i.e., increased ROS production, reduced antioxidant capacity, and/or decreased NO bioactivity) can sensitize TGF whereas states with increased NO formation can attenuate the TGF response. In the JGA, particularly in the macula densa cells, the NOS1β plays an important role in the regulation of TGF. (B) Abnormal expression and function of this splice variant of NOS1 have been associated with several cardiovascular, renal, and metabolic disorders (e.g., hypertension, preeclampsia, kidney disease, and diabetes). Much knowledge regarding the regulation of NOS1β expression and its interaction with other enzyme systems in the JGA (e.g., NOX2), as well as downstream signaling, have been obtained from experimental animal models with chronic high‐salt diet treatment and infusion of subpressor doses of angiotensin II (Ang II) using osmotic minipumps. Figure was created with BioRender.com.
Figure 2. Figure 2. The balance between nitric oxide synthase 1 (NOS1)‐derived nitric oxide NO) and NADPH oxidase 2 (NOX2)‐derived superoxide (O2−) formation importantly influence the responsiveness of the tubuloglomerular feedback (TGF). Emerging evidence has demonstrated that among the different splice variants of NOS1, the β‐version expressed in macula densa cells is of particular importance in the regulation of TGF. Numerous factors and conditions have been associated altered function and expression of NOS1β and NADPH oxidase 2 (NOX2). (A) Chronic dietary high‐salt (NaCl) intake, as well as high levels of angiotensin II (Ang II) and hypertension, has been associated with increased NOX2, which to some extent can be balanced by increased NOS1β expression. Ang II, via activation of its type 1 receptor (AT1) stimulates NOX2, whereas activation of its type 2 receptor (AT2) inhibits NOX2 and may also activate NOS1β. Altered balance between AT1 and AT2 receptor expression/activation, in favor of the latter, has been suggested to protect young‐to‐middle‐aged females from Ang II‐induced pathophysiological events. Moreover, in chronic conditions with hyperglycemia (diabetes mellitus), the sodium‐glucose transporter‐2 and ‐1 (SGLT2 and SGLT1) in the proximal tubules may be saturated, leading to activation of SGLT1 in the macula densa cells in the thick ascending limb. Here, SGLT1 activation has been associated with increased expression and activity of the NOS1β splice variant. (B) Reduced expression of NOS1β and/or high production of O2− is associated with decreased NO bioactivity and increased TGF response, which leads to contraction of the afferent arteriole and reduction of glomerular pressure. In pathological conditions, this has been associated with reduced kidney function (glomerular filtration rate, GFR), retention of salt and fluid, and hence elevated blood pressure (hypertension). (C) Increased expression of NOS1β and/or low production of O2− is associated with increased NO bioactivity and decreased TGF response, which leads to dilatation of the afferent arteriole and increase of glomerular pressure. In pathological conditions, this has been associated with increased GFR (hyperfiltration), development of glomerular and tubular injuries, and kidney disease. Figure was created with BioRender.com.


Figure 1. (A) The kidney via its functional units, the nephrons, importantly contribute to maintain body fluid and electrolyte homeostasis. Tubuloglomerular feedback (TGF) is operating within the juxtaglomerular apparatus (JGA), which consists of specialized structures/cells in the region between the thick ascending limb (TAL) of the loop of Henle and the distal convoluted tubule, near the afferent arteriole. TGF is initiated via mechanisms located to the macula densa sense and reacts in response to changes in tubular lumen NaCl. At high NaCl load, a paracrine signal is generated and transferred from macula densa in the TAL to the adjacent endothelial and vascular smooth muscle cells of the afferent arteriole. Tuning of the TGF is modulated by the activity of the enzyme isoforms nitric oxide synthase 1 (NOS1) and NAD(P)H oxidase 2 (NOX). The former enzyme exists in three different splice variants, that is alpha (α), beta (β), and gamma (γ), which all are known to generate nitric oxide (NO). Bioavailability and signaling of NOS1‐derived NO are dampened, via scavenging, by NOX2‐derived reactive oxygen species (ROS) including superoxide (O2−). Conditions with oxidative stress (i.e., increased ROS production, reduced antioxidant capacity, and/or decreased NO bioactivity) can sensitize TGF whereas states with increased NO formation can attenuate the TGF response. In the JGA, particularly in the macula densa cells, the NOS1β plays an important role in the regulation of TGF. (B) Abnormal expression and function of this splice variant of NOS1 have been associated with several cardiovascular, renal, and metabolic disorders (e.g., hypertension, preeclampsia, kidney disease, and diabetes). Much knowledge regarding the regulation of NOS1β expression and its interaction with other enzyme systems in the JGA (e.g., NOX2), as well as downstream signaling, have been obtained from experimental animal models with chronic high‐salt diet treatment and infusion of subpressor doses of angiotensin II (Ang II) using osmotic minipumps. Figure was created with BioRender.com.


Figure 2. The balance between nitric oxide synthase 1 (NOS1)‐derived nitric oxide NO) and NADPH oxidase 2 (NOX2)‐derived superoxide (O2−) formation importantly influence the responsiveness of the tubuloglomerular feedback (TGF). Emerging evidence has demonstrated that among the different splice variants of NOS1, the β‐version expressed in macula densa cells is of particular importance in the regulation of TGF. Numerous factors and conditions have been associated altered function and expression of NOS1β and NADPH oxidase 2 (NOX2). (A) Chronic dietary high‐salt (NaCl) intake, as well as high levels of angiotensin II (Ang II) and hypertension, has been associated with increased NOX2, which to some extent can be balanced by increased NOS1β expression. Ang II, via activation of its type 1 receptor (AT1) stimulates NOX2, whereas activation of its type 2 receptor (AT2) inhibits NOX2 and may also activate NOS1β. Altered balance between AT1 and AT2 receptor expression/activation, in favor of the latter, has been suggested to protect young‐to‐middle‐aged females from Ang II‐induced pathophysiological events. Moreover, in chronic conditions with hyperglycemia (diabetes mellitus), the sodium‐glucose transporter‐2 and ‐1 (SGLT2 and SGLT1) in the proximal tubules may be saturated, leading to activation of SGLT1 in the macula densa cells in the thick ascending limb. Here, SGLT1 activation has been associated with increased expression and activity of the NOS1β splice variant. (B) Reduced expression of NOS1β and/or high production of O2− is associated with decreased NO bioactivity and increased TGF response, which leads to contraction of the afferent arteriole and reduction of glomerular pressure. In pathological conditions, this has been associated with reduced kidney function (glomerular filtration rate, GFR), retention of salt and fluid, and hence elevated blood pressure (hypertension). (C) Increased expression of NOS1β and/or low production of O2− is associated with increased NO bioactivity and decreased TGF response, which leads to dilatation of the afferent arteriole and increase of glomerular pressure. In pathological conditions, this has been associated with increased GFR (hyperfiltration), development of glomerular and tubular injuries, and kidney disease. Figure was created with BioRender.com.
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Article Title: The Role of Macula Densa Nitric Oxide Synthase 1 Beta Splice Variant in Modulating Tubuloglomerular Feedback
 

How to Cite

Ruisheng Liu, Luis A. Juncos, Yan Lu, Jin Wei, Jie Zhang, Lei Wang, En Y. Lai, Mattias Carlstrom, A. Erik G. Persson. The Role of Macula Densa Nitric Oxide Synthase 1 Beta Splice Variant in Modulating Tubuloglomerular Feedback. Compr Physiol 2023, 13: 4215-4229. doi: 10.1002/cphy.c210043