Renal Vascular Smooth Muscle NaV Channels: Regulation and Contribution to Hypoperfusion in Neonatal Ischemic Acute Kidney Injury - Voltage-gated sodium (NaV) channels are essential membrane proteins that mediate sodium ion (Na⁺) influx in response to membrane depolarization. This rapid Na⁺ entry is critical for generating and propagating action potentials in excitable cells, including neurons, skeletal muscle, and cardiac muscle. The nine functionally characterized NaV isoforms (NaV1.1–NaV1.9), encoded by SCN genes, exhibit distinct tissue distributions and physiological functions. Mutations in NaV channels contribute to a range of neonatal and adult diseases, highlighting their role in pathological processes. While their contributions to neuronal and cardiac excitability are well established, NaV channels are also expressed in the vasculature, where their pathophysiological significance remains unclear. Although NaV channels have been identified in mesenteric, pulmonary, coronary, and femoral arteries, their regulation and function in the renal preglomerular microvasculature remain unexplored. Our preliminary findings suggest that NaV1.5 contributes to the regulation of intrarenal arterial tone in the neonatal kidney, revealing a previously underappreciated role for this channel in neonatal vascular physiology. In neonatal pig renal vascular smooth muscle cells (VSMCs), NaV1.5 channels are spatially localized in close proximity to the Na⁺-Ca²⁺ exchanger (NCX). Activation of NaV channels promotes Ca²⁺ influx and vasoconstriction through reverse-mode NCX activity and L-type Ca²⁺ channels (LTCCs). Additionally, hypoxia/reoxygenation (H/R) stimulates contraction of the neonatal pig renal artery through the NaV-NCX-LTCC axis. Our pilot studies further suggest that nitric oxide (NO) regulates NaV1.5 expression in neonatal renal VSMCs via the forkhead box protein O1 signaling pathway, a mechanism that may drive alterations in endothelial-to-VSMC signal transduction and contribute to renal ischemia-reperfusion (IR)-induced hypoperfusion—a key factor in the development of acute kidney injury (AKI). This project aims to (1) elucidate the regulation of NaV1.5 expression and activity in renal VSMCs by NO-dependent signaling; (2) determine the role of NaV1.5 in H/R-induced intracellular Na⁺ and Ca²⁺ overload in renal VSMCs and its contribution to renal vasoconstriction; and (3) assess whether NaV-mediated increases in renal vascular resistance contribute to IR-induced kidney hypoperfusion and AKI. To accomplish these objectives, we will employ a multidisciplinary approach that integrates biochemical analyses, liquid chromatography-tandem mass spectrometry, intracellular ion measurements, patch-clamp electrophysiology, vessel myography, and neonatal pig models of renal IR. We will evaluate the therapeutic potential of clinical NaV channel modulators and utilize a transgenic SCN5A neonatal pig model. Findings from this study will provide fundamental insights into the regulatory mechanisms and functional significance of renal vascular NaV1.5, establishing its potential as a therapeutic target for mitigating neonatal AKI.
