The microcirculation of the renal medulla traps NaCI and urea deposited to the interstitium by the loops of Henle and collecting ducts and distributes blood flow to a hypoxic region of the kidney. Substantial evidence has linked medullary perfusion to renal regulation of salt and water excretion and genesis of acute renal failure. Descending vasa recta (DVR) are 15 um diameter arteriolar microvessels through which blood flow reaches the medulla. DVR are surrounded by smooth muscle / pericytes that impart contractile properties to regulate vasoactivity. We have now established methods to study Ca 2+ signaling and channel architecture of the DVR pericyte. Using those methods we have shown that pericytes depolarize through activation of a Ca 2+-dependent CI- conductance and inhibition of K+ channels. These events accompany angiotensin II induced vasoconstriction. To advance our understanding of the physiology of the DVR pericyte, we propose the following aims:
Aim 1) We will examine the physiological properties of the Ca 2+-dependent CI- conductance that regulates pericyte membrane potential. We will determine the anion selectivity and sensitivity to inhibitors of whole cell currents and the 11 pS CICa channel we previously identified. We will test the roles of protein kinase C and protein kinase A in the activation and inactivation of the rat pericyte CICa channel.
Aim 2) We will examine pericyte Kv channel suppression by angiotensin II (Angll). We will test the cation selectivity of Angll suppressible whole cell currents. We will determine the cation selectivity and activation mechanisms of a 58 pS Kv channel that Angll suppresses in cell attached patches.
Aim 3) We will test the role of 20-HETE to mediate Angll induced DVR vasoconstriction and Kv channel inhibition. We will test the role of 20-HETE to regulate pericyte membrane potential and suppress K+ channels.
Aim 4) We will determine which pathways participate in Ca 2+ entry in DVR pericytes. We will examine the current voltage characteristics and cation selectivity of Ca 2+ entry pathways opened by Ca 2+store depletion. We will test the hypothesis that voltage operated Ca 2+ entry participates in pericyte signaling. We will determine the role of VOCC and nonselective cation channels in Angll signaling and test a role for protein kinase C in their activation.
|Zhang, Zhong; Payne, Kristie; Pallone, Thomas L (2016) Descending Vasa Recta Endothelial Membrane Potential Response Requires Pericyte Communication. PLoS One 11:e0154948|
|Zhang, Zhong; Lin, Hai; Cao, Chunhua et al. (2014) Descending vasa recta endothelial cells and pericytes form mural syncytia. Am J Physiol Renal Physiol 306:F751-63|
|Pallone, Thomas L (2014) Complex vascular bundles, thick ascending limbs, and aquaporins: wringing out the outer medulla. Am J Physiol Renal Physiol 306:F505-6|
|Zhang, Zhong; Payne, Kristie; Pallone, Thomas L (2014) Syncytial communication in descending vasa recta includes myoendothelial coupling. Am J Physiol Renal Physiol 307:F41-52|
|Zhang, Zhong; Payne, Kristie; Cao, Chunhua et al. (2013) Mural propagation of descending vasa recta responses to mechanical stimulation. Am J Physiol Renal Physiol 305:F286-94|
|Khurana, Sandeep; Raina, Hema; Pappas, Valeria et al. (2012) Effects of deoxycholylglycine, a conjugated secondary bile acid, on myogenic tone and agonist-induced contraction in rat resistance arteries. PLoS One 7:e32006|
|Khurana, Sandeep; Raufman, Jean-Pierre; Pallone, Thomas L (2011) Bile acids regulate cardiovascular function. Clin Transl Sci 4:210-8|
|Edwards, Aurelie; Cao, Chunhua; Pallone, Thomas L (2011) Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta. Am J Physiol Renal Physiol 300:F441-56|
|Zhang, Zhong; Lin, Hai; Cao, Chunhua et al. (2010) Voltage-gated divalent currents in descending vasa recta pericytes. Am J Physiol Renal Physiol 299:F862-71|
|Lin, Hai; Pallone, Thomas L; Cao, Chunhua (2010) Murine vasa recta pericyte chloride conductance is controlled by calcium, depolarization, and kinase activity. Am J Physiol Regul Integr Comp Physiol 299:R1317-25|
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