High-Protein Diet–Induced Glomerular Hyperfiltration Is Dependent on Neuronal Nitric Oxide Synthase β in the Macula Densa via Tubuloglomerular Feedback Response

A high protein intake is associated with increased glomerular filtration rate (GFR), which has been suggested to be mediated by reduced signaling of the tubuloglomerular feedback (TGF) mechanism. Nitric oxide (NO) has been shown to contribute to high protein-induced glomerular hyperfiltration, but the specific NO synthase (NOS) isoform responsible is not clear. In this study, a model for high-protein-induced hyperfiltration in conscious mice was developed. Using this model, we investigated the role of TGF using adenosine A1-receptor knockout mice lacking the TGF mechanism. Furthermore, the role of the different NOS isoforms was studied using neuronal-, inducible-, and endothelial-NOS knockout mice, and furthermore, wild-type mice acutely administered with the unspecific NOS inhibitor Nω-nitro-l-arginine methyl ester (100 mg/kg). GFR was measured consecutively in mice given a low-protein diet (8% casein) for 10 days, followed by a high-protein diet (50% casein) for 10 days. All mice developed high protein-induced hyperfiltration to a similar degree. These results demonstrate that high protein-induced glomerular hyperfiltration is independent of the TGF mechanism and NOS isoforms.

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Role of the macula densa sodium glucose cotransporter type 1-nitric oxide synthase 1-tubuloglomerular feedback pathway in diabetic hyperfiltration.

Kidney International ◽

10.1016/j.kint.2021.10.037 ◽

2021 ◽

Author(s):

Jie Zhang ◽

Jing Cai ◽

Yu Cui ◽

Shan Jiang ◽

Jin Wei ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Macula Densa ◽

Tubuloglomerular Feedback ◽

Sodium Glucose Cotransporter ◽

Nitric Oxide Synthase 1 ◽

Oxide Synthase ◽

Feedback Pathway

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Neuronal nitric oxide synthase modulates rat renal microvascular function

AJP Renal Physiology ◽

10.1152/ajprenal.1998.274.3.f516 ◽

1998 ◽

Vol 274 (3) ◽

pp. F516-F524 ◽

Cited By ~ 39

Author(s):

Atsuhiro Ichihara ◽

Edward W. Inscho ◽

John D. Imig ◽

L. Gabriel Navar

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Neuronal Nitric Oxide Synthase ◽

Macula Densa ◽

Ang Ii ◽

Sprague Dawley ◽

Vasoconstrictor Response ◽

Arteriolar Tone ◽

Oxide Synthase

This study was performed to determine the influence of neuronal nitric oxide synthase (nNOS) on renal arteriolar tone under conditions of normal, interrupted, and increased volume delivery to the macula densa segment and on the microvascular responses to angiotensin II (ANG II). Experiments were performed in vitro on afferent (21.2 ± 0.2 μm) and efferent (18.5 ± 0.2 μm) arterioles of kidneys harvested from male Sprague-Dawley rats, using the blood-perfused juxtamedullary nephron technique. Superfusion with the specific nNOS inhibitor, S-methyl-l-thiocitrulline (l-SMTC), decreased afferent and efferent arteriolar diameters, and these decreases in arteriolar diameters were prevented by interruption of distal volume delivery by papillectomy. When 10 mM acetazolamide was added to the blood perfusate to increase volume delivery to the macula densa segment, afferent arteriolar vasoconstrictor responses tol-SMTC were enhanced, but this effect was again completely prevented after papillectomy. In contrast, the arteriolar diameter responses to the nonselective NOS inhibitor, N ω-nitro-l-arginine (l-NNA) were only attenuated by papillectomy.l-SMTC (10 μM) enhanced the efferent arteriolar vasoconstrictor response to ANG II but did not alter the afferent arteriolar vasoconstrictor responsiveness to ANG II. In contrast, l-NNA (100 μM) enhanced both afferent and efferent arteriolar vasoconstrictor responses to ANG II. These results indicate that the modulating influence of nNOS on afferent arteriolar tone of juxtamedullary nephrons is dependent on distal tubular fluid flow. Furthermore, nNOS exerts a differential modulatory action on the juxtamedullary microvasculature by enhancing efferent, but not afferent, arteriolar responsiveness to ANG II.

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Role of macula densa neuronal nitric oxide synthase in renal diseases

Medical Molecular Morphology ◽

10.1007/s00795-006-0310-2 ◽

2006 ◽

Vol 39 (1) ◽

pp. 2-7 ◽

Cited By ~ 19

Author(s):

Akihiro Tojo ◽

Maristela Lika Onozato ◽

Toshiro Fujita

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Neuronal Nitric Oxide Synthase ◽

Macula Densa ◽

Renal Diseases ◽

Oxide Synthase

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Lack of contribution of nitric oxide synthase to cholinergic vasodilation in murine renal afferent arterioles

AJP Renal Physiology ◽

10.1152/ajprenal.00433.2017 ◽

2018 ◽

Vol 314 (6) ◽

pp. F1197-F1204 ◽

Cited By ~ 3

Author(s):

Sungmi Park ◽

Benjamin J. Bivona ◽

Lisa M. Harrison-Bernard

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Knockout Mice ◽

Neuronal Nitric Oxide Synthase ◽

Macula Densa ◽

Afferent Arteriole ◽

Wild Type ◽

Afferent Arterioles ◽

Nos Inhibitor ◽

Oxide Synthase

We have previously reported significant increases in neuronal nitric oxide synthase (NOS) immunostaining in renal arterioles of angiotensin type 1A receptor (AT1A) knockout mice, and in arterioles and macula densa cells of AT1A/AT1B knockout mice. The contribution of nitric oxide derived from endothelial and macula densa cells in the maintenance of afferent arteriolar tone and acetylcholine-induced vasodilation was functionally determined in kidneys of wild-type, AT1A, and AT1A/AT1B knockout mice. Acetylcholine-induced changes in arteriolar diameters of in vitro blood-perfused juxtamedullary nephrons were measured during control conditions, in the presence of the nonspecific NOS inhibitor, Nω-nitro-l-arginine methyl ester (NLA), or the highly selective neuronal NOS inhibitor, N5-(1-imino-3-butenyl)-l-ornithine (VNIO). Acetylcholine (0.1 mM) produced a significant vasoconstriction in afferent arterioles of AT1A/AT1B mice (−10.9 ± 5.1%) and no changes in afferent arteriolar diameters of AT1A knockout mice. NLA (0.01–1 mM) or VNIO (0.01–1 μM) induced significant dose-dependent vasoconstrictions (−19.8 ± 4.0% 1 mM NLA; −7.8 ± 3.5% 1 μM VNIO) in afferent arterioles of kidneys of wild-type mice. VNIO had no effect on afferent arteriole diameters of AT1A knockout or AT1A/AT1B knockout mice, suggesting nonfunctional neuronal nitric oxide synthase. These data indicate that acetylcholine produces a significant renal afferent arteriole vasodilation independently of nitric oxide synthases in wild-type mice. AT1A receptors are essential for the manifestation of renal afferent arteriole responses to neuronal nitric oxide synthase-mediated nitric oxide release.

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