Connexin 40 Mediates the Tubuloglomerular Feedback Contribution to Renal Blood Flow Autoregulation

Abstract

Connexins are important in vascular development and function. Connexin 40 (Cx40), which plays a predominant role in the formation of gap junctions in the vasculature, participates in the autoregulation of renal blood flow (RBF), but the underlying mechanisms are unknown. Here, Cx40-deficient mice (Cx40-ko) had impaired steady-state autoregulation to a sudden step increase in renal perfusion pressure. Analysis of the mechanisms underlying this derangement suggested that a marked reduction in tubuloglomerular feedback (TGF) in Cx40-ko mice was responsible. In transgenic mice with Cx40 replaced by Cx45, steady-state autoregulation and TGF were weaker than those in wild-type mice but stronger than those in Cx40-ko mice. N-Nitro-L-arginine-methyl-ester (L-NAME) augmented the myogenic response similarly in all genotypes, leaving autoregulation impaired in transgenic animals. The responses of renovascular resistance and arterial pressure to norepinephrine and acetylcholine were similar in all groups before or after L-NAME inhibition. Systemic and renal vasoconstrictor responses to L-NAME were also similar in all genotypes. We conclude that Cx40 contributes to RBF autoregulation by transducing TGF-mediated signals to the afferent arteriole, a function that is independent of nitric oxide (NO). However, Cx40 is not required for the modulation of the renal myogenic response by NO, norepinephrine-induced renal vasoconstriction, and acetylcholine-or NO-induced vasodilation.

Role of connexin40 in the autoregulatory response of the afferent arteriole

“…1, B and D). Cx40 KO mice have been reported to also lose their expression of Cx37 in endothelial cells from cremaster arterioles and renal arteries (7,26,27). In the present study, expression of Cx37 also seemed reduced in endothelial cells in the afferent arteriole from Cx40 KO mice (Fig.…”

“…Renal vascular expression of Cx40 is primarily restricted to endothelial cells, mesangial cells, and renin-secreting granular cells (1,19,26). We also found expression of Cx40 in these cell types in the WT mice (Fig.…”

“…Despite the increased arterial pressure of the Cx40 KO mice, RBF is normal, but renal autoregulation is attenuated (26).…”

“…Based on an analysis of the dynamics of the autoregulatory response, Just et al (26) concluded that it was primarily the TGF component of renal autoregulation that was affected by deletion of the Cx40 gene although an effect on the myogenic component could not be excluded. Inhibition of gap junctional communication using connexin mimetic peptides against Cx37 and -43 significantly reduced the myogenic response in mesenteric arterioles from rats (10).…”

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

“…The present finding that plasma renin activity was similar between ZDF and ZL rats may account at least in part for the acute effects of angiotensin inhibition on glomerular hypertension in diabetes [48] and make it unlikely that renin-angiotensin system played a role in deteriorated TGFback in ZDF rats. Cx40-deficient mice lack the pressure control of renin release and TGFback contribution to renal blood flow autoregulation [10,49]. Cx37 and Cx40 are involved in control of renin release and TGFback in Wistar rats [11,12].…”