Arendshorst Lab - Research

Function of Renal Vascular Smooth Muscle Cells: Receptors and Signal Transduction Pathways

More than 70 million Americans have hypertension, a major cardiovascular risk factor, highly predictive of other vascular diseases such as atherosclerosis, renal failure, ischemic coronary dysfunction, stroke, and diabetes mellitus. The molecular basis of hypertension is complex, involving multiple genes and environmental factors that interact in a complex manner. The kidneys play a central role in regulating arterial pressure (AP), and severe renal disease is accompanied by hypertension. Common renal abnormalities during the development of hypertension are exaggerated renal vascular reactivity to vasoconstrictor agents, oxidative stress and endothelial dysfunction with attenuated responses to vasodilator factors, causing or acting in concert with abnormal renal retention of salt and water.

vascular smooth muscle cell
Fig. 1. Working model of ADPR cyclase-mediated-Ca2+ signaling in afferent arteriolar VSMC. For the sake of simplicity, Ca2+ entry channels (L-type, store-operated, receptor operated) and other ion channels (e.g., K and Cl) have been omitted. “ADPR cyclase” represents the novel renal ADPR cyclase and conventional CD38. Click for larger view.

The major resistance vessels in the kidney, the afferent and efferent arterioles, are regulated by a constellation of neuro-humoral agents (e.g., angiotensin II (Ang II), norepinephrine (NE)) acting in concert with paracrine/autacrine factors (e.g., Ang II, thromboxane (TxA2), •O2-, nitric oxide (NO)), largely through stimulation of G-protein coupled receptors (GPCR). How these multiple regulatory systems interact to impact on Ca2+ signaling in the renal microcirculation is poorly understood. As the renal vasculature is pivotal in the regulation of fluid and electrolyte balance, it is imperative to more comprehensively understand its regulation.

Vasomotor tone is determined by changes in [Ca2+]i and Ca2+ sensitivity of the contractile proteins. Changes in [Ca2+]i are achieved via Ca2+ entry from the extracellular space and mobilization from intracellular stores. We recently broke new ground in demonstrating that ADPR cyclase/ryanodine receptor (RyR)/Ca2+-induced Ca2+ release (CICR) is a critical second messenger system regulating Ca2+ signaling and vasoconstriction in the renal microcirculation. This system is rapidly activated by both GPCR and myogenic stimuli and plays a central role in amplifying vascular smooth muscle cell (VSMC) cytosolic Ca2+ concentration ([Ca2+]i) responses to a variety of agonists (Fig. 1). CD38 is the major ADPR cyclase regulating renal blood flow (RBF) in the renal microcirculation. We hypothesize that CD38 functions as the major ADPR cyclase regulating RyR-mediated Ca2+ mobilization and reactivity in renal microvessels in both health and disease. Our current research objectives are to provide new insights into the ADPR cyclase/RyR/CICR signal transduction pathway and advance our understanding of the physiological role of this system in the renal vasculature. We postulate that the renal vasculature is less reactive to vasoconstrictor agents in the absence of CD38 and this affords protection against the hypertensive actions of Ang II and other vasoconstrictors. To test this, we perform Ca2+ signaling studies on afferent arterioles isolated from CD38-/- and WT mice, and then extend our findings to the in vivo setting where we integrate how these cellular mechanisms contribute to renal vasoconstriction, establishing functional significance in physiology and during the pathogenesis of hypertension produced by chronic Ang II infusion. We use pharmacological tools in combination with CD38 gene-targeted mice to investigate this critical Ca2+ signaling pathway and its role in the regulation of renal vascular function and blood pressure.

Bill Arendshorst is a member of NIH Reviewers Reserve and serves on the Editorial Board of American Journal of Hypertension, Therapeutic Advances in Cardiovascular Disease and World Journal of Nephrology.