Hypertension affects 60 million adults in the United States, and is a major independent risk factor for stroke, myocardial infarction, and congestive heart failure, and a major cause of end-stage renal disease. More than half of hypertensive patients have a salt-sensitive component, and in approximately 30%, hypertension is predominantly due to abnormalities in sodium handling by the kidney. The kinases SPAK and OSR1 play important roles in the regulation of renal sodium transport. In vitro, both kinases activate the sodium transporters NKCC2 and NCC, but little is known about the pathways via which SPAK and OSR1 activate them in whole animals. Studies in mice indicate that OSR1 is more important for activation of NKCC2, while SPAK is the main activator of NCC. Recent evidence shows that multiple forms of SPAK and OSR1 exist in the kidney, some of which inhibit sodium transport, contrary to the prevailing view that SPAK and OSR1 only activate it. Stimuli that lower blood pressure (e.g. dietary salt restriction), or administration of hormones that increase blood pressure (e.g. aldosterone, vasopressin and angiotensin II), reduce the levels of inhibitory SPAK and OSR1, but increase levels of activating forms. Regulation of renal sodium transport and blood pressure by SPAK and OSR1 is thus more complex than previously believed. The objective of this proposal is to determine the mechanisms by which SPAK and OSR1 regulate renal sodium transport. The R01 Grant will provide the necessary resources for the principal investigator to test the hypothesis that SPAK and OSR1 isoforms differentially regulate renal sodium transport, and differentially mediate responses to physiological stimuli that alter blood pressure. To test this hypothesis, three specific aims are proposed.
Aim 1 is to examine the mechanisms by which SPAK and OSR1 isoforms differentially regulate renal sodium transport. The mechanisms by which SPAK and OSR1 isoforms inhibit activity of NKCC2 will be determined using Xenopus oocytes and mammalian cells.
Aim 2 is to identify the physiological factors that modulate isoform expression. Using wild-type, SPAK knockout and renal OSR1 knockout mice, the effects of sodium restriction, aldosterone infusion and induced-hypertension on the levels and renal localization of SPAK and OSR1 isoforms, as well as the mechanism and timing of these effects, will be determined.
Aim 3 is to examine how SPAK and OSR1 regulate renal sodium transport and blood pressure in whole animals. The effects of acute and chronic aldosterone, vasopressin or angiotensin II administration on NCC and NKCC2 phosphorylation and activity will be determined in wild-type, SPAK knockout and renal OSR1 knockout mice. Mice lacking both SPAK and OSR1 in the kidney will also be characterized. These studies will enable us to assign specific physiological functions to either SPAK or OSR1 isoforms, a significant advance towards understanding how two closely related kinases that activate the same targets in vitro have very different roles in vivo. In addition, we will gain insight into the pathways that activate cation cotransporters independently of SPAK/OSR1.
Hypertension affects 60 million adults in the United States and is a major independent risk factor for stroke, myocardial infarction, and congestive heart failure, and a major cause of end-stage renal disease. The degree of sodium reabsorption by the kidney is the key determinant of blood pressure, but the mechanisms by which sodium reabsorption is regulated are incompletely understood. By studying the mechanisms by which the kidney reabsorbs sodium, we can learn more about the causes of hypertension, and design new therapies to treat the large number of American adults (about 6 million) whose hypertension is currently uncontrollable.
| Terker, Andrew S; Castañeda-Bueno, Maria; Ferdaus, Mohammed Z et al. (2018) With no lysine kinase 4 modulates sodium potassium 2 chloride cotransporter activity in vivo. Am J Physiol Renal Physiol 315:F781-F790 |
| Ferdaus, Mohammed Z; McCormick, James A (2018) Mechanisms and controversies in mutant Cul3-mediated familial hyperkalemic hypertension. Am J Physiol Renal Physiol 314:F915-F920 |
| Saritas, Turgay; Puelles, Victor G; Su, Xiao-Tong et al. (2018) Optical Clearing in the Kidney Reveals Potassium-Mediated Tubule Remodeling. Cell Rep 25:2668-2675.e3 |
| Nelson, Jonathan W; Ferdaus, Mohammed Z; McCormick, James A et al. (2018) Endothelial transcriptomics reveals activation of fibrosis-related pathways in hypertension. Physiol Genomics 50:104-116 |
| Wang, Ming-Xiao; Cuevas, Catherina A; Su, Xiao-Tong et al. (2018) Potassium intake modulates the thiazide-sensitive sodium-chloride cotransporter (NCC) activity via the Kir4.1 potassium channel. Kidney Int 93:893-902 |
| Ferdaus, Mohammed Z; Miller, Lauren N; Agbor, Larry N et al. (2017) Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects. JCI Insight 2: |
| Cuevas, Catherina A; Su, Xiao-Tong; Wang, Ming-Xiao et al. (2017) Potassium Sensing by Renal Distal Tubules Requires Kir4.1. J Am Soc Nephrol 28:1814-1825 |
| Blankenstein, K I; Borschewski, A; Labes, R et al. (2017) Calcineurin inhibitor cyclosporine A activates renal Na-K-Cl cotransporters via local and systemic mechanisms. Am J Physiol Renal Physiol 312:F489-F501 |
| McCormick, James A; Ellison, David H (2017) Nephron Remodeling Underlies Hyperkalemia in Familial Hyperkalemic Hypertension. J Am Soc Nephrol 28:2555-2557 |
| Ferdaus, Mohammed Z; McCormick, James A (2016) The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy. Am J Physiol Renal Physiol 310:F1389-96 |
Showing the most recent 10 out of 16 publications
