William J. Arendshorst, PhD
Professor

Education:

PhD, Indiana University 1970

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

My laboratory is interested in function of vascular smooth muscle cells responsible for the regulation of renal blood flow and glomerular filtration rate in the kidney in health and disease. A variety of approaches are employed to investigate how the vascular smooth muscle cells (VSMC) of the afferent arteriole produce changes in cytosolic calcium concentration and contraction in response to physical forces such as hydrostatic pressure and stretch, local paracrine agents such as angiotensin II and prostanoids, and circulating hormones such as vasopressin.

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We have found that kidney and nephron function are abnormal in young rats during the development of spontaneous hypertension of genetic origin, which is a model of essential hypertension in humans. A major focus of our current research is on determining the mechanisms responsible for exaggerated vascular reactivity to angiotensin II, vasopressin, and tubuloglomerular feedback stimulation we have found in rats with genetic hypertension. One abnormality under investigation concerns defective buffering of vasoconstriction by the dilator prostanoids, most likely due to weak coupling of prostanoid receptors to a GTP-binding protein leading to weak stimulation of cAMP. Another abnormality we are studying is the regulation of vasopressin receptors in VSMC which is set to a higher level in hypertensive-prone animals. Homologous and heterologous regulation of angiotensin II and vasopressin receptors is determined in vivo and in vitro. Parallel studies on arterioles and vascular smooth muscle cells from normotensive and hypertensive animals are designed to provide new information about how these systems function in normal cells as well as advancing our understanding of aberrant control systems in disease.

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Whole kidney blood flow is measured via electromagnetic flowmetry in anesthetized rat or mouse to assess vascular reactivity in vivo. Localized perfusion in cortical and medullary regions of the kidney is determined by laser doppler flowmetry. Afferent arteriolar regulation of glomerular function via a unique tubuloglomerular feedback mechanism involving the juxtaglomerular apparatus is determined at the single nephron level in an anesthetized animals using micropuncture techniques. At the cellular level, we are currently utilizing two preparations of VSMC: freshly isolated from the afferent arteriole and those grown in cell culture. Receptor expression is being studied in cultured VSMC of renal resistance vessels using radioligand binding methods in combination with RT-PCR methods and RNAse protection assays.

Another major thrust of our research is mechanisms mediating the regulation of cytosolic calcium concentration by various signal transduction pathways at the organ levels and in individual cells. Cytosolic calcium concentration in VSMC is measured by fura-2 fluorescence using a microscope-based dual wavelength photometer. Signaling mediated by receptors is assessed by pharmacological antagonists and by elimination of specific receptor types or subtypes via gene targeting in mice.

Bill Arendshorst is a member of NIH Reviewers Reserve and serves on the Editorial Board of American Journal of Hypertension, the American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, and Hypertension.

Recent Publications:

Just A, AJM Olson, CL Whitten and WJ Arendshorst.  Superoxide mediates acute renal vasoconstriction produced by angiotensin II and catecholamines by a mechanism independent of nitric oxide.  Am J Physiol - Heart Circ Physiol 292: H83-H92, 2007.  

Peng Z, Dang A, Arendshorst WJ. Increased expression and activity of phospholipase C in renal arterioles of young spontaneously hypertensive rats. Am J Hypertens. 2007 Jan;20(1):38-43.

Fellner SK and WJ Arendshorst.  Endothelin-A and -B receptors, superoxide, and Ca²⁺ signaling in afferent arterioles.  Am J Physiol - Renal Physiol 292: F175-F184, 2007.

Fellner SK and WJ Arendshorst.  Voltage-gated Ca²⁺ entry and ryanodine receptor Ca²⁺ -induced Ca2+ release in preglomerular arterioles.  Am J Physiol - Renal Physiol 292:  F1568-F1572, 2007. 

Peng Z and WJ Arendshorst.  PLC expression and activity in smooth muscle cells of renal arterioles and aorta of young SHR during culture.  Am J Hypertens 20: 520-526, 2007. 

Vågnes O, BM Iversen and WJ Arendshorst.  Short-term Ang II produces renal vasoconstriction independent of TP receptor activation and TxA2 / isoprostane production.  Am J Physiol - Renal Physiol 293: F860-F867, 2007. 

Peng Z and WJ Arendshorst.  Activation of phospholipase Cγ1 protects renal arteriolar VSMCs from H2O2-induced cell death.  Kidney Blood Pressure Res 31: 1-9, 2007.

Thai T, SK Fellner and WJ Arendshorst.  ADP-ribosyl cyclase and ryanodine receptor activity contribute to basal renal vasomotor tone and agonist-induced renal vasoconstriction in vivo.  Am J Physiol - Renal Physiol 293: F1107-F1114, 2007. 

Just A and WJ Arendshorst.  Novel mechanisms of renal blood flow autoregulation and the autoregulatory role of A1 adenosine receptors in mice.  Am J Physiol - Renal Physiol 293: F1489-F1500, 2007. 

Fellner SK and WJ Arendshorst.  Angiotensin II-stimulated calcium entry mechanisms in afferent arterioles:  Role of transient receptor potential canonical channels and reverse Na+/Ca 2+ exchange.  Am J Physiol - Renal Physiol, In Press.  Epub 10/31/2007. 

Boffa, JJ, and WJ Arendshorst. (2005) Maintenance of renal vascular reactivity contributes to acute renal failure during endotoxemic shock. J Amer Soc Nephrol 16: 117-124.

Fellner, SK and WJ Arendshorst. (2005) Angiotensin II Ca²⁺ signaling in rat afferent arterioles: Stimulation of cyclic ADP ribose and IP3 pathways. Am J Physiol Renal Physiol 288: F785-F791.

Just, A, AJM Olson, JR Falck, WJ Arendshorst. (2005) Nitric oxide and NO-independent mechanisms mediate ETB receptor buffering of ET-1-induced renal vasoconstriction in the rat. Am J Physiol Regul Integr Comp Physiol 288: R1168-R1177.

Just A and WJ Arendshorst. (2005) Nitric Oxide blunts myogenic autoregulation in rat renal but not skeletal muscle circulation via tubuloglomerular feedback. J Physiol 569: 959-974.

Vagnes, O, FH Hansen, JJ Feng, BM Iversen, and WJ Arendshorst. (2005) Enhanced Ca²⁺ responds to AVP in preglomerular vessels from rats with genetic hypertension during different hydration states. Am J Physiol – Renal Physiol 288: F1249-F1256.

Facemire, C, WJ Arendshorst. (2005) Calmodulin mediates norepinephrine-induced receptor-operated calcium in preglomerular resistance arteries. Am J Physiol Renal Physiol 289: F127-F136.

Fellner, SK and WJ Arendshorst. (2005) Angiotensin II, reactive oxygen species and Ca²⁺ signaling in afferent arterioles. Am J Physiol Renal Physiol. 289: F1012-F1019.

Just A, AJM Olson, and WJ Arendshorst. (2004) Dual constrictor and dilator actions of ETB receptors in the rat renal microcirculation: Interactions with ETA receptors. Am. J. Physiol. Renal Physiol. 286 (4): F660-F668.

Salomonsson, M, and WJ Arendshorst. (2004) Effect of tyrosine kinase blockade on norepinephrine-induced cytosolic calcium response in rat afferent arterioles. Am. J. Physiol. – Renal Physiol 286(5): F866-F874, 2004.

Salomonsson, M, CM Sorensen, WJ Arendshorst, J Steendahl, and N-H Holstein-Rathlou. (2004) Calcium handling in afferent arterioles. Acta Physiol. Scand. 181: 421-429.

Fellner, SK and WJ Arendshorst. (2004) Endothelin A and B receptors on preglomerular vascular smooth muscle cells. Kidney Int 65: 1810-1817.

Boffa, JJ, A Just, and WJ Arendshorst. (2004) Thromboxane receptor mediates renal vasoconstriction and contributes to acute renal failure in endotoxemic mice. J Amer Soc Nephrol 15: 2358-2365. (Note Basic Science Highlight on p. 2343).