The medulla of the kidney is a hypoxic environment that is exclusively perfused by descending vasa recta (DVR). Salt transporting nephrons and collecting ducts in the medulla are vulnerable to injury. In addition to vasodilatory paracrine signaling, the DVR wall is a syncytium wherein myo- endothelial gap junctions provide a conduit for endothelium dependent hyperpolarization. Moreover, DVR endothelial syncytia can transmit signals along the DVR axis to dilate feeding vessels and enhance nutrient blood flow. We show, for the first time, that renal ischemia preconditions DVR endothelia and pericytes. They become hyperpolarized, conduct hyperpolarizing currents more effectively and increase generation of NO. DVR vasoconstriction is blunted. We will investigate these changes and their mechanisms with the following aims.
Aim 1 will test the roles of NOS isoforms and other endothelium dependent relaxing factors in the blunted vasoconstriction observed after ischemic preconditioning. We will test whether the endothelium is needed to sustain pericyte hyperpolarization. We will test whether mural conduction of pericyte depolarization and cytoplasmic calcium responses is inhibited.
Aim 2 will test for modification of gap junction coupling and ion channel activity after ischemic preconditioning. We will test mural conductance by electrophysiology and intercellular tracer diffusion. We will examine expression of connexin proteins and determine whether selective blockade with Gap mimetic peptides alters mural conduction. We will measure monovalent ion channel activity that determines membrane potential and test whether reduced contraction is accompanied by inhibition of voltage gated Ca2+ and Na+ channel activity.
Aim 3 will focus on the pathways involved in ischemic and toxic DVR preconditioning. We will test whether direct ischemia is mimicked by remote hindlimb ischemia or erythropoietin treatment. We will test whether recovery from toxic injury from gentamicin modifies DVR. We will test whether increasing the activity of hypoxia inducible factors prevents endothelial dysfunction and mimics the DVR adaptations conferred by ischemic preconditioning.

Public Health Relevance

The medulla of the kidney processes salts and water for elimination into the urine. Due to the arrangement of its blood vessels the medulla has a low oxygen concentration and is vulnerable to injury. Blood flow to the medulla is provided entirely by Descending Vasa Recta (DVR), very small vessels that constrict and dilate to regulate medullary blood flow. Cells of the DVR wall, called pericytes and endothelia, are controlled by ion channels and coupled together through 'gap junctions'. We will study how those pathways are modified when the kidney is subject to injury through reduction of blood flow or toxins.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Kidney Molecular Biology and Genitourinary Organ Development (KMBD)
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Ketchum, Christian J
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University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
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Zhang, Zhong; Payne, Kristie; Pallone, Thomas L (2018) Adaptive responses of rat descending vasa recta to ischemia. Am J Physiol Renal Physiol 314:F373-F380
Zhang, Zhong; Payne, Kristie; Pallone, Thomas L (2016) Descending Vasa Recta Endothelial Membrane Potential Response Requires Pericyte Communication. PLoS One 11:e0154948
Palant, Carlos E; Chawla, Lakhmir S; Faselis, Charles et al. (2016) High serum creatinine nonlinearity: a renal vital sign? Am J Physiol Renal Physiol 311:F305-9
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
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