βENaC Acts as a Mechanosensor in Renal Vascular Smooth Muscle Cells That Contributes to Renal Myogenic Blood Flow Regulation, Protection From Renal Injury and Hypertension

Abstract

Pressure-induced constriction (also known as the “myogenic response”) is an important mechanodependent response in small renal arteries and arterioles. The response is initiated by vascular smooth muscle cell (VSMC) stretch due to an increase in intraluminal pressure and leads to vasoconstriction. The myogenic response has two important roles as a mechanism of local blood flow autoregulation and protection against systemic blood pressure-induced microvascular damage. However, the molecular mechanisms underlying initiation of myogenic response are unresolved. Although several molecules have been considered initiators of the response, our laboratory has focused on the role of degenerin proteins because of their strong evolutionary link to mechanosensing in the nematode. Our laboratory has addressed the hypothesis that certain degenerin proteins act as mechanosensors in VSMCs. This article discusses the importance of a specific degenerin protein, β Epithelial Na+ Channel (βENaC), in pressure-induced vasoconstriction, renal blood flow and susceptibility to renal injury. We propose that loss of the renal myogenic constrictor response delays the correction of renal blood flow that occurs with fluctuations in systemic pressure, which allows pressure swings to be transmitted to the microvasculature, thus increasing the susceptibility to renal injury and hypertension. The role of βENaC in myogenic regulation is independent of tubular βENaC and thus represents a non-tubular role for βENaC in renal-cardiovascular homeostasis.

The angiotensin II type I receptor contributes to impaired cerebral blood flow autoregulation caused by placental ischemia in pregnant rats

“…Another possibility may relate to evidence showing that AngII reduces immunolabeled βENaC in renal vascular smooth muscle [30]. This is potentially important because βENaC is an essential component of the vascular mechanosensor that contributes to the myogenic response [31], and we previously showed that βENaC protein expression is lower in cerebral arteries from placental ischemic rats when compared with normal pregnant rats [17]. Therefore, if cerebral vascular responses to AngII mirror those in the renal vasculature, it may be that angiotensin mediated downregulation of βENaC is a contributing mechanism.…”

Myogenic Tone in Peripheral Resistance Arteries and Arterioles: The Pressure Is On!

“…A number of ion channels have been proposed to contribute to pressure-induced depolarization of VSMCs (Harder, 1984;Knot and Nelson, 1998;Kotecha and Hill, 2005) including: members of the transient receptor potential (TRP)-family of cation channels, such as TRPC6 (Welsh et al, 2002;Gonzales et al, 2014), TRPM4 (Earley et al, 2004;Gonzales et al, 2014), TRPV2 (McGahon et al, 2016), and TRPV4 (Soni et al, 2017); members of the degenerin family of channels including the epithelial Na + channel (ENaC) family Drummond, 2005, 2006;VanLandingham et al, 2009;Drummond and Stec, 2015), the acid-sensitive ion channel (ASIC) family of channels (Gannon et al, 2015), and purinergic P 2 X 7 Purinergic Receptor (P 2 X 7 ) channels (Kauffenstein et al, 2016; Figure 2). In addition, Ca 2+ -activated Cl − channels (CaCC; ANO1/TMEM16A) may be activated by Ca 2+ influx through TRPC6 channels (Bulley et al, 2012;Wang et al, 2016) and also contribute to pressureinduced depolarization of VSMCs (Figure 2).…”

High‐resolution imaging of the actin cytoskeleton and epithelial sodium channel, CFTR, and aquaporin‐9 localization in the vas deferens

“…The expression of ENaC in smooth muscle cells has been shown in many organs including vascular smooth muscle (Drummond, Grifoni, & Jernigan, 2008; Kusche‐Vihrog, Tarjus, Fels, & Jaisser, 2014), epididymis (Sharma & Hanukoglu, 2019), arrector pili muscle cells in skin (Hanukoglu et al, 2017), and renal microvascular smooth muscle cells (Guan, Pollock, Cook, Hobbs, & Inscho, 2009). It has been suggested that ENaC functions as a mechanosensor in vascular smooth muscle cells that initiate pressure‐induced constriction known as the “myogenic response” (Drummond & Stec, 2015). Extending these earlier findings, we suggest that ENaC has a role in the function of vas deferens smooth muscle cells that remain to be defined.…”