ENaC Proteins as Mediators of Renal Myogenic Constriction

The myogenic response is an intrinsic vascular response characterized by vasoconstriction in response to increases and vasodilation to decreases in perfusion pressure. Recent studies suggest this response may play a significant role in the protection of the renal microcirculation from pressure dependent injury, especially with concomitant renal disease.1 Although the myogenic response was first described more than 100 years ago, the molecular mechanisms underlying the transduction of pressure into a cellular event (ie, vasoconstriction) in vascular smooth muscle cells (VSMCs) has remained elusive. Several potential molecules with a connection to mechanosensitive responses have been identified including integrins, transient receptor potential (TRP) channels, and members of the Epithelial Na Channel (ENaC) family.2 Members of the ENaC family have received recent attention because of evidence for and against a role for ENaC proteins in myogenic constriction in the renal circulation. The current study by Guan et al helps to address the controversial role of ENaC in afferent arteriolar myogenic constriction.3 ENaC and closely related Acid Sensing Ion Channel (ASIC) proteins are considered potential mechanotransducers in VSMCs because of their strong evolutionary connection to a group of proteins termed degenerins. The degenerins are a group of nematode Caenorhabditis elegans proteins that comprise the ion channel pore in a large multimeric mechanosensory complex.4 Genetic evidence suggests the pore forming degenerins are tethered to the cytoskeleton and extracellular matrix and aid in force transduction.4 The extracellular matrix, linking proteins, and cytoskeletal proteins are required for proper mechanosensor channel activation.4 An analogous mechanotransducer model in mammals has also been proposed (Figure 1A).5 Although many scientists consider ENaC proteins to be restricted to epithelial cells, ENaC expression has been repeatedly identified in many other cells types, including VSMCs.5 Several studies support a role for ENaC proteins as mediators of myogenic responsiveness in renal interlobar and middle cerebral arteries. ENaC proteins are expressed in VSMCs from several circulatory systems. Furthermore, ENaC inhibition (amiloride or its lipophilic analog benzamil) or gene silencing (using overexpression of dominant-negative ENaC isoforms or siRNA) blocks myogenic constriction in response to an increase in pressure.5 At least pharmacological blockade also blocks resting myogenic tone.6 Thus, the initial studies on the role of ENaC as a mediator of myogenic response in renal vessels suggest ENaC proteins may act as mediators of myogenic response. A schematic illustrating the potential role of ENaC in myogenic constriction based on our current understanding of myogenic signaling cascade is provided in Figure 1B. A limitation of these studies is that they were conducted in renal interlobar arteries (50 to 100 m resting diameter). While interlobar arteries have a myogenic response, the major site of renal vascular resistance is the afferent arteriole. The myogenic response can be studied in afferent arterioles using isolated arterioles and whole kidney approaches, however each approach presents individual challenges. Studies in isolated afferent arterioles are technically demanding, and isolating the afferent arteriole from the surrounding extracellular matrix may disrupt components of the gating mechanism (noted in the preceding paragraph), so negative results from studies with this approach may not be informative. The importance of ENaC in myogenic constriction has not been addressed using this model. Studies using whole kidney perfusion approaches are also possible, but care must be taken to prevent contribution of the tubuloglomerular feedback mechanism (TGF, pressure-dependent increases in Na delivery to macula densa cells elicits afferent arteriolar vasoconstriction). The hydronephrotic kidney and the juxtamedullary nephron preparation are 2 models that allow for whole kidney evaluation of afferent myogenic responses. In the hydronephrotic kidney, chronic (6 to 8 weeks) uretal ligation induces tubular atrophy, which abolishes TGF and allows visualization of the afferent arterioles.7 Using this preparation, a recent study by Wang et al demonstrated no contribution of ENaC to myogenic function in rat afferent arterioles and further demonstrated little to no message for ENaC transcripts in isolated afferent arterioles.7 Findings of this study do not support a role for ENaC proteins in afferent arteriole myogenic constriction. However, the recent findings of Guan et al stand in contrast to those of Wang et al. Guan et al localized expression of ENaC proteins in preglomerular VSMCs using immunolocalization and demonstrated pharmacological ENaC blockade inhibited myogenic constriction in rat afferent arterioles using an isolated blood-perfused juxtamedullary nephron preparation in which effects of TGF were eliminated by a papillectomy. So, what factor(s) might explain the contrasting results? Although the answer to this question is not clear, one possibility is the animal model (hydronephrotic kidney versus juxtamedullary nephron prepFrom the Department of Physiology, University of Mississippi Medical Center, Jackson. Correspondence to Heather A. Drummond, PhD, Associate Professor, Department of Physiology, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216. E-mail hdrummond@physiology. umsmed.edu (Hypertension. 2009;54:962-963.) © 2009 American Heart Association, Inc.