The microcirculation of the renal medulla traps NaCl and urea to facilitate urinary concentration and supplies metabolites to mitigate hypoxia. Descending vasa recta (DVR) are 15 mm diameter arteriolar microvessels that supply all blood flow to the medulla. Through contraction of abluminal smooth muscle / pericytes, DVR regulate medullary perfusion. We have established methods to study contraction, Ca2+ signaling and ion channel architecture of the pericytes. Depolarization of pericyte membrane potential opens voltage gated cation entry channels that conduct Na+ (NaV) or Ca2+ (CaV). In turn, depolarization occurs through a combination of Ca2+ dependent Cl- channel (CaCC) activation and K+ channel inhibition. We provide evidence that DVR cation conductance is heavily regulated by NO and heme oxygenase (HO) and that it is modified in Dahl salt sensitive rats and eNOS null mice. We will study the regulation of DVR pericyte CaV by intrinsic activity of nitric oxide synthase (NOS) and HO in normal and hypertensive rodent models.
Aim 1 will test the regulation of DVR pericyte CaV by nitric oxide synthase (NOS) and NO. We will identify which CaV subclasses are suppressed by NO and which NOS isoforms generate NO in the DVR wall of rats and eNOS / nNOS null mice. The relevant signaling pathways involved will be delineated. Finally, a role for the DVR NaV conductance will be studied with respect to its operation in Ca2+ conducting "slip mode" or in concert with Na+/Ca2+ exchange.
Aim 2 will study the regulation of DVR pericyte CaV by heme oxygenase / CO. We will test the ability of HO activation and suppression to modify CaV conductance, membrane potential and vessel contraction. We will employ methods to upregulate and reduce expression of HO- 1 in vivo to test the consequences on DVR channel activity and contractility.
Aim 3 will examine alteration of pericyte voltage gated Ca2+ entry pathways in salt sensitive hypertension. We will determine which channel conductances account for the depolarized state of Dahl/SS pericytes. We will measure rates of NO generation and study the consequences of supplying L-arginine, a maneuver known to reverse paucity of medullary NO generation. We will test whether upregulation of HO-1 normalizes CaV conductance and membrane potential in Dahl/SS rats and examine the ability of intramedullary CaV blockade to augment perfusion of the medulla in those animals.

Public Health Relevance

The kidney has an outer region called the cortex and an inner region called the medulla. Descending vasa recta (DVR) are microvessels that supply all blood flow to the medulla. Blood flow to the medulla is important for control of salt and water excretion into the urine, urinary concentration of the urine, modulation of blood pressure and protection from kidney injury. The DVR have smooth muscle like cells, called pericytes, that contract to regulate their diameter and thus, blood flow to the medulla. The extent of that contraction depends on the flow of ions across the pericyte cell membrane. Chloride and calcium ions play pivotal roles. The pathways that carry those ions into the cell are highly regulated by molecules such as nitric oxide, carbon dioxide and oxidant molecules. This project is to determine the identity and regulation of those transport routes in health and hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067621-12
Application #
8322021
Study Section
Special Emphasis Panel (ZRG1-DKUS-L (03))
Program Officer
Ketchum, Christian J
Project Start
1999-07-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
12
Fiscal Year
2012
Total Cost
$333,863
Indirect Cost
$116,363
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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; 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
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
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
Khurana, Sandeep; Raufman, Jean-Pierre; Pallone, Thomas L (2011) Bile acids regulate cardiovascular function. Clin Transl Sci 4:210-8
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
Cao, Chunhua; Edwards, Aurelie; Sendeski, Mauricio et al. (2010) Intrinsic nitric oxide and superoxide production regulates descending vasa recta contraction. Am J Physiol Renal Physiol 299:F1056-64

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