Previous studies demonstrate a role for β epithelial Na⁺ channel (βENaC) protein as a mediator of myogenic constriction in renal interlobar arteries. However, the importance of βENaC as a mediator of myogenic constriction in renal afferent arterioles, the primary site of development of renal vascular resistance, has not been determined. We colocalized βENaC with smooth muscle α-actin in vascular smooth muscle cells in renal arterioles using immunofluorescence. To determine the importance of βENaC in myogenic constriction in renal afferent arterioles, we used a mouse model of reduced βENaC (βENaC m/m) and examined pressure-induced constrictor responses in the isolated afferent arteriole-attached glomerulus preparation. We found that, in response to a step increase in perfusion pressure from 60 to 120 mmHg, the myogenic tone increased from 4.5 ± 3.7 to 27.3 ± 5.2% in +/+ mice. In contrast, myogenic tone failed to increase with the pressure step in m/m mice (3.9 ± 0.8 to 6.9 ± 1.4%). To determine the importance of βENaC in myogenic renal blood flow (RBF) regulation, we examined the rate of change in renal vascular resistance following a step increase in perfusion pressure in volume-expanded animals. We found that, following a step increase in pressure, the rate of myogenic correction of RBF is inhibited by 75% in βENaC m/m mice. These findings demonstrate that myogenic constriction in afferent arterioles is dependent on normal expression of βENaC.

Previous studies from our laboratory have suggested that degenerin proteins contribute to myogenic constriction, a mechanism of blood flow regulation and protection against pressure-dependent organ injury, in renal vessels. The goal of the present study was to determine the importance of one family member, acid-sensing ion channel 2 (ASIC2), in myogenic constriction of renal interlobar arteries, myogenic regulation of whole kidney blood flow, renal injury, and blood pressure using ASIC2^+/+, ASIC2^+/−, and ASIC2^−/− mice. Myogenic constriction in renal interlobar arteries was impaired in ASIC2^+/− and ASIC2^−/− mice, whereas constriction to KCl/phenylephrine was unchanged. Correction of whole kidney renal vascular resistance (RVR) during the first 5 s after a 10- to 20-mmHg step increase in perfusion pressure, a timeframe associated with myogenic-mediated correction of RVR, was slowed (4.2 ± 0.9, 0.3 ± 0.7, and 2.4 ± 0.3 resistance units/s in ASIC2^+/+, ASIC2^+/−, and ASIC2^−/− mice). Although modest reductions in function were observed in ASIC2^−/− mice, greater reductions were observed in ASIC2^+/− mice, which may be explained by protein-protein interactions of ASIC2 with other degenerins. Isolated glomeruli from ASIC2^+/− and ASIC2^−/− mice had modest alterations in the expression of inflammation and injury markers (transforming growth factor-β, mouse anti-target of antiproliferative antibody-1, and nephrin), whereas ASIC2^+/− mice had an increase in the remodeling marker collagen type III. Consistent with a more severe loss of function, mean arterial pressure was increased in ASIC2^+/− mice (131 ± 3 mmHg) but not in ASIC2^−/− mice (122 ± 3 vs. 117 ± 2 mmHg in ASIC2^+/+ mice). These results suggest that ASIC2 contributes to transduction of the renal myogenic response and are consistent with the protective role of myogenic constriction against renal injury and hypertension.

Myogenic constrictor responses in small renal arteries and afferent arterioles are suppressed in mice with reduced levels of β-epithelial Na⁺channel (βENaC^m/m). The underlying mechanism is unclear. Decreased activity of voltage-gated calcium channels (VGCC) or mechanically gated ion channels and increased activity of large conductance calcium-activated potassium (BK) channels are a few possible mechanisms. The purpose of this study was to determine if VGCC, BK, or mechanically gated ion channel activity was altered in renal vascular smooth muscle cell (VSMC) from βENaC^m/mmice. To address this, we used whole cell patch-clamp electrophysiological approaches in freshly isolated renal VSMCs. Compared with βENaC^+/+controls, the current-voltage relationships for VGCC and BK activity are similar in βENaC^m/mmice. These findings suggest neither VGCC nor BK channel dysfunction accounts for reduced myogenic constriction in βENaC^m/mmice. We then examined mechanically gated currents using a novel in vitro assay where VSMCs are mechanically activated by stretching an underlying elastomer. We found the mechanically gated currents, predominantly carried by Na⁺, are observed with less frequency (87 vs. 43%) and have smaller magnitude (−54.1 ± 12.5 vs. −20.9 ± 4.9 pA) in renal VSMCs from βENaC^m/mmice. Residual currents are expected in this model since VSMC βENaC expression is reduced by 50%. These findings suggest βENaC is required for normal mechanically gated currents in renal VSMCs and their disruption may account for the reduced myogenic constriction in the βENaC^m/mmodel. Our findings are consistent with the role of βENaC as a VSMC mechanosensor and function of evolutionarily related nematode degenerin proteins.

Pressure-induced constriction (also known as the “myogenic response”) is an important mechano-dependent response in certain blood vessels. The response is mediated by vascular smooth muscle cells (VSMCs) and characterized by a pressure-induced vasoconstriction in small arteries and arterioles in the cerebral, mesenteric, cardiac, and renal beds. The myogenic response has two important roles; it is a mechanism of blood flow autoregulation and provides protection against systemic blood pressure-induced damage to delicate microvessels. However, the molecular mechanism(s) underlying initiation of myogenic response is unclear. Degenerin proteins have a strong evolutionary link to mechanotransduction in the nematode. Our laboratory has addressed the hypothesis that these proteins may also act as mechanosensors in certain mammalian tissues such as VSMCs and arterial baroreceptor neurons. This article discusses the importance of a specific degenerin protein, β Epithelial Na⁺ Channel (βENaC) in pressure-induced vasoconstriction in renal vessels and arterial baroreflex function as determined in a mouse model of reduced βENaC (βENaC m/m). We propose that loss of baroreflex sensitivity (due to loss of baroreceptor βENaC) increases blood pressure variability, increasing the likelihood and magnitude of upward swings in systemic pressure. Furthermore, loss of the myogenic constrictor response (due to loss of VSMC βENaC) will permit those pressure swings to be transmitted to the microvasculature in βENaC m/m mice, thus increasing the susceptibility to renal injury and hypertension.

Previous studies suggest β-epithelial Na⁺channel protein (β-ENaC) may mediate myogenic constriction, a mechanism of blood flow autoregulation. A recent study demonstrated that mice with reduced levels of β-ENaC (β-ENaC m/m) have delayed correction of whole kidney blood flow responses, suggesting defective myogenic autoregulatory capacity. Reduced renal autoregulatory capacity is linked to renal inflammation, injury, and hypertension. However, it is unknown whether β-ENaC m/m mice have any complications associated with reductions in autoregulatory capacity such as renal inflammation, injury, or hypertension. To determine whether the previously observed altered autoregulatory control was associated with indicators of renal injury, we evaluated β-ENaC m/m mice for signs of renal inflammation and tissue remodeling using marker expression. We found that inflammatory and remodeling markers, such as IL-1β, IL-6, TNF-α, collagen III and transforming growth factor-β, were significantly upregulated in β-ENaC m/m mice. To determine whether renal changes were associated with changes in long-term control of blood pressure, we used radiotelemetry and found that 5-day mean arterial blood pressure (MAP) was significantly elevated in β-ENaC m/m (120 ± 3 vs. 105 ± 2 mmHg, P = 0.016). Our findings suggest loss of β-ENaC is associated with early signs of renal injury and increased MAP.

Heme oxygenase (HO) plays an important role in the cardiovascular system. It is involved in many physiological and pathophysiological processes in all organs of the cardiovascular system. From the regulation of blood pressure and blood flow to the adaptive response to end-organ injury, HO plays a critical role in the ability of the cardiovascular system to respond and adapt to changes in homeostasis. There have been great advances in our understanding of the role of HO in the regulation of blood pressure and target organ injury in the last decade. Results from these studies demonstrate that targeting of the HO system could provide novel therapeutic opportunities for the treatment of several cardiovascular and renal diseases. The goal of this review is to highlight the important role of HO in the regulation of cardiovascular and renal function and protection from disease and to highlight areas in which targeting of the HO system needs to be translated to help benefit patient populations.