Blunted Tubuloglomerular Feedback by Absence of Angiotensin Type 1A Receptor Involves Neuronal NOS

Abstract

Abstract-To define the role of angiotensin type 1A (AT 1A ) receptor in modulating tubuloglomerular feedback signals and to determine its relationship to neuronal NO synthase (nNOS), the diameter of the afferent arterioles of wild-type and AT 1A receptor-deficient mice was measured by the blood-perfused juxtamedullary nephron technique. The afferent arteriolar diameter of wild-type and AT 1A receptor-deficient mice averaged 16.7Ϯ0.6 (nϭ9) and 16.8Ϯ0.7 m (nϭ9), respectively. In the wild-type mice, addition of 10 mol/L acetazolamide to the blood perfusate exerted a biphasic afferent arteriolar constriction, with the initial response and sustained response averaging 47.2Ϯ3.8% and 33.9Ϯ3.3%, respectively. In AT 1A receptor-deficient mice, the initial response and sustained response averaged 51.6Ϯ3.6% and 9.5Ϯ1.3%, respectively, and the sustained response was significantly attenuated compared with that of wild-type mice. Inhibition of nNOS with 10 mol/L S-methyl-L-thiocitrulline significantly decreased the afferent arteriolar diameter of AT 1A receptor-deficient mice, from 15.1Ϯ1.2 to 5.0Ϯ0.3 m (nϭ7), and the decrease was significantly greater than that observed in wild-type mice (from 15.9Ϯ1.2 to 10.6Ϯ1.3 m; nϭ8). During nNOS inhibition, the initial and sustained afferent arteriolar constrictor responses to acetazolamide in wild-type mice averaged 54.4Ϯ6.4% and 44.8Ϯ11.3%; respectively, and were similar to those in AT 1A receptor-deficient mice (53.2Ϯ6.4% and 59.5Ϯ4.4%, respectively). These results suggest that AT 1A receptors enhance tubuloglomerular feedback-mediated afferent arteriolar constriction, at least in part, through reducing the counteracting modulation by nNOS. Key Words: arterioles Ⅲ autoregulation Ⅲ mice Ⅲ nitric oxide synthase Ⅲ receptors, angiotensin II T he tubuloglomerular feedback (TGF) mechanism is recognized as the main mechanism responsible for the intrarenal vascular resistance adjustments that occur in response to increases in distal volume and sodium chloride/ bicarbonate delivery. 1 Peritubular perfusion of angiotensin II enhances TGF responses, 2 and TGF responses do not occur in angiotensin type 1A (AT 1A ) receptor-deficient mice 3 or in ACE-deficient mice. 4 These findings suggest that angiotensin II is a significant constituent of the TGF control system.Immunohistochemical studies have demonstrated the specific localization of neuronal NO synthase (nNOS) in macula densa cells, 5,6 which serve as the sensing site of the TGF mechanism by monitoring flow-mediated changes in tubular fluid composition to the distal nephron and, in turn, by releasing vasoactive paracrine signals that alter afferent arteriolar resistance. 1 NO produced in response to activation of macula densa nNOS affects the diameter of afferent and efferent arterioles 7 and contributes to the counteracting resetting process of the TGF-mediated autoregulatory response, resulting in a biphasic afferent arteriolar constriction. 8 Thus, macula densa nNOS activity plays an important role in the counteracting modulation of TGF ...

Alterations in Renal Endothelial Nitric Oxide Synthase Expression by Salt Diet in Angiotensin Type-1a Receptor Gene Knockout Mice

“…Moreover, AtgϪ/Ϫ mice have been shown to have pathophysiologic conditions associated with increased diuresis and sodium/water loss (26). Ichihara et al (27) demonstrated that the attenuation of the TGF response observed in At1aϪ/Ϫ mice involved enhanced counteracting modulation by the influence of nNOS possibly derived from macula densa. On the other hand, Patzak et al (28) demonstrated that mainly endotheliumderived NO counteracts AngII-induced vasoconstriction of iso- Renal cortical eNOS protein expression in At1aϩ/ϩ mice and At1aϪ/Ϫ mice.…”

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

“…39 Enhanced tubuloglomerular feedback responses may be the result of an angiotensin IIinduced reduction in local levels of nitric oxide. 40 Tubulo-glomerular feedback responses have been reported to be enhanced in spontaneously hypertensive rats, 41 but there are few reports regarding to tubulo-glomerular feedback in DS rats. It is well accepted that DS rats on high-salt diet exhibit a suppressed systemic RAS (renninangiotensin system) accompanied with inappropriately activated renal RAS.…”

Renal Renin-Angiotensin System

“…In addition, the expression of the nNOS gene and protein in the macula densa are upregulated in angiotensinogen-gene-knockout mice [39] and AT1 receptor-deficient mice [40]. Interestingly, the enhanced ability of nNOS-derived NO to counteract the TGF-mediated afferent arteriolar constriction observed in AT1 receptor-deficient mice [41], suggests that the modulation of TGF responses by Ang II is partially due to decreased activity of macula densa nNOS.…”