Abstract P128: Enhanced NOS1β in the Macula Densa Contributes to the Diabetic Hyperfiltration

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Jin Wei ◽  
Jie Zhang ◽  
Gensheng Zhang ◽  
Lei Wang ◽  
Shaohui Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Glucose ◽  
Splice Variants ◽  
Mrna Level ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Early Diabetes ◽  
Bolus Intravenous Injection ◽  
Oxide Synthase

Hyperfiltration is common in early diabetes and considered a risk factor for diabetic nephropathy. Inhibited tubuloglomerular feedback (TGF) mediated by less NaCl delivery at the macula densa contributes to the diabetic hyperfiltration. Nitric oxide (NO) released from macula densa via neuronal nitric oxide synthase (NOS1) inhibits TGF response. We recently demonstrated the significance of TGF response in the long-term control of GFR, sodium excretion and blood pressure, mediated by macula densa NOS1β. However, whether the NOS1β-mediated TGF response play an important role in the diabetic hyperfiltration is unknown. We hypothesized that macula densa NOS1β is upregulated in diabetes, which blunts TGF response and contributes to the diabetic hyperfiltration. The mice with deletion of NOS1 specifically from the macula densa (MD-NOS1KO) and wild-type C57BL/6 (WT) mice were used. Diabetes was induced by alloxan (55 mg/kg i.v.) with blood glucose from 350 to 450 mg/dl. Expression of NOS1 splice variants was measured with real-time PCR and Western blot. GFR was measured by plasma FITC-inulin clearance following a single bolus intravenous injection in conscious mice. GFR increased by 24.7% in diabetic WT mice (from 241.60±19.73 to 301.35±21.76 μl/min) and only by 16.5% in diabetic MD-NOS1KO mice (from 236.61±16.12 to 275.61±11.73 μl/min) (n=6/group, p<0.01 vs baseline; p<0.05 vs WT). To determine whether glucose induces hyperfiltration mediated by macula densa NOS1, intravenous infusion of 2 μl/g glucose solution (2 M) into non-diabetic C57BL/6 mice elevated blood glucose to about 350 mg/dl and increased GFR by 19.1% (from 236±15.4 to 281±9.7 μl/min, n=6, p<0.05), but did not significantly increase GFR (from 223±6.9 to 240±15.7 μl/min) in non-diabetic MD-NOS1KO mice (n=6, p<0.01 vs WT). The expression of NOS1β was upregulated by 8.9±1.3 folds in protein level and 10.1±2.1 folds in mRNA level in diabetic WT mice (n=4, p<0.01). Present study provided a novel mechanism for diabetic hyperfiltration mediated by macula densa NOS1β. Enhanced NOS1β in the macula densa contributes to the diabetic hyperfiltration.

scholarly journals Nitric oxide release as an essential mitigating step in tubuloglomerular feedback: observations during intrarenal nitric oxide clamp.

1998 ◽  
Vol 9 (9) ◽  
pp. 1596-1603
Author(s):  
E Turkstra ◽  
B Braam ◽  
H A Koomans
Keyword(s):  
Nitric Oxide ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Sprague Dawley ◽  
Arginine Infusion ◽  
Nitric Oxide Release ◽  
Sprague Dawley Rats ◽  
Flow Pressure ◽  
Oxide Synthase ◽  
Nitroprusside Infusion

Nitric oxide synthase inhibition in the kidney enhances tubuloglomerular feedback (TGF) responsiveness. This may reflect either the effect of reduced basal nitric oxide (NO) availability or the effect of impaired NO release that is physiologically induced by TGF activation. However, it is unknown whether the latter actually takes place. In this study, it was hypothesized that NO is released (from macula densa cells or endothelium) as part of the normal TGF loop, and mitigates the TGF response. In Sprague Dawley rats, TGF responsiveness was assessed (fall in tubular stop flow pressure, deltaSFP, upon switching loop of Henle perfusion rates from 0 to 40 nl/min) during an intrarenal NO clamp (systemic infusion of nitro-L-arginine, 10 microg/kg per min, followed by intrarenal nitroprusside infusion adjusted to restore renal blood flow [RBF]). This maneuver was presumed to fix intrarenal NO impact at a physiologic level. To validate the approach, TGF responsiveness during an intrarenal angiotensin II (AngII) clamp (systemic infusion of enalaprilat 0.2 mg/kg per min, followed by intrarenal AngII infusion) was also studied. AngII is presumed to modulate but not mediate, TGF, thus not to increase as part of the TGF loop. In untreated animals, RBF was 7.4 +/- 0.4 ml/min, and deltaSFP was 5.7 +/- 1.6 mmHg. Nitro-L-arginine infusion alone reduced RBF to 5.3 +/- 0.5 ml/min (P < 0.05); with nitroprusside infusion, RBF was restored to 8.3 +/- 0.7 ml/min. In this condition (NO clamp), deltaSFP was markedly increased to 19.6 +/- 3.2 mmHg (P < 0.05). By contrast, deltaSFP, which was virtually abolished during enalaprilat alone (0.2 +/- 0.3 mmHg), was not significantly different from controls during AngII clamp (8.2 +/- 1.0 mmHg). These data suggest that NO may well be released upon TGF activation. By contrast, AngII is not dynamically involved in TGF activation, but may modulate the TGF response. Thus, dynamic release of NO during TGF activation mitigates the TGF response, so that it will offset the action of a primary, as yet undefined, vasoconstrictor mediator. The source of this NO, macula densa or endothelium, remains to be elucidated.

scholarly journals Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

2019 ◽  
Vol 30 (4) ◽  
pp. 578-593 ◽  
Author(s):  
Jie Zhang ◽  
Jin Wei ◽  
Shan Jiang ◽  
Lan Xu ◽  
Lei Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Knockout Mice ◽  
Kidney Tissue ◽  
Human Kidney ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Glomerular Hyperfiltration ◽  
Early Diabetes

BackgroundGlomerular hyperfiltration is common in early diabetes and is considered a risk factor for later diabetic nephropathy. We propose that sodium-glucose cotransporter 1 (SGLT1) senses increases in luminal glucose at the macula densa, enhancing generation of neuronal nitric oxide synthase 1 (NOS1)–dependent nitric oxide (NO) in the macula densa and blunting the tubuloglomerular feedback (TGF) response, thereby promoting the rise in GFR.MethodsWe used microperfusion, micropuncture, and renal clearance of FITC–inulin to examine the effects of tubular glucose on NO generation at the macula densa, TGF, and GFR in wild-type and macula densa–specific NOS1 knockout mice.ResultsAcute intravenous injection of glucose induced hyperglycemia and glucosuria with increased GFR in mice. We found that tubular glucose blunts the TGF response in vivo and in vitro and stimulates NO generation at the macula densa. We also showed that SGLT1 is expressed at the macula densa; in the presence of tubular glucose, SGLT1 inhibits TGF and NO generation, but this action is blocked when the SGLT1 inhibitor KGA-2727 is present. In addition, we demonstrated that glucose increases NOS1 expression and NOS1 phosphorylation at Ser1417 in mouse renal cortex and cultured human kidney tissue. In macula densa–specific NOS1 knockout mice, glucose had no effect on NO generation, TGF, and GFR.ConclusionsWe identified a novel mechanism of acute hyperglycemia–induced hyperfiltration wherein increases in luminal glucose at the macula densa upregulate the expression and activity of NOS1 via SGLT1, blunting the TGF response and promoting glomerular hyperfiltration.

Selective neuronal nitric oxide synthase inhibition blocks furosemide-stimulated renin secretion in vivo

1995 ◽  
Vol 269 (1) ◽  
pp. F134-F139 ◽  
Author(s):  
W. H. Beierwaltes
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Nitric Oxide Synthase ◽  
Perfusion Pressure ◽  
Renal Perfusion ◽  
Macula Densa ◽  
Renin Secretion ◽  
Renal Perfusion Pressure ◽  
Neuronal Nos ◽  
Oxide Synthase

The macula densa is a regulatory site for renin. It contains exclusively the neuronal isoform of nitric oxide synthase (NOS), suggesting NO could stimulate renin secretion through the macula densa pathway. To test whether neuronal NOS mediates renin secretion, renin was stimulated by either the renal baroreceptor or the diuretic furosemide (acting through the macula densa pathway). Renin secretion rate (RSR) was measured in 12 Inactin-anesthetized rats at normal (104 +/- 3 mmHg) and reduced renal perfusion pressure (65 +/- 1 mmHg), before and after selective blockade of the neuronal NOS with 7-nitroindazole (7-NI, 50 mg/kg ip). 7-NI had no effect on basal blood pressure (102 +/- 2 mmHg) or renal blood flow (RBF). Decreasing renal perfusion pressure doubled RSR from 11.8 +/- 3.3 to 22.9 +/- 5.7 ng ANG I.h-1.min-1 (P < 0.01) (ANG I is angiotensin I). Similarly, in 7-NI-treated rats, reduced perfusion doubled RSR from 8.5 +/- 1.8 to 20.5 +/- 6.2 ng ANG I.h-1.min-1 (P < 0.01). Renal hemodynamics and RSR were measured in response to 5 mg/kg iv furosemide in 12 control rats and 11 rats treated with 7-NI. Blocking neuronal NOS did not alter blood pressure (102 +/- 2 mmHg), RBF (5.8 +/- 0.4 ml.min-1.g kidney wt-1), or renal vascular resistance (18.7 +/- 1.4 mmHg.ml-1.min.g kidney wt).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Splice variants of neuronal nitric oxide synthase are present in the rat kidney

2008 ◽  
Vol 24 (5) ◽  
pp. 1422-1428 ◽  
Author(s):  
C. Smith ◽  
M. Merchant ◽  
A. Fekete ◽  
H.-L. Nyugen ◽  
P. Oh ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Splice Variants ◽  
Rat Kidney ◽  
Neuronal Nitric Oxide Synthase ◽  
Oxide Synthase
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