The School of Medicine newsletter will spotlight a recently published faculty research paper in each issue. The goal is to highlight the great research, policy, and other work happening at OHSU and to share this information across departments and disciplines. A list of all papers compiled by the OHSU Library and published by OHSU faculty during the prior month will also be provided here in each issue.
The inaugural paper-of-the-month was published in the Journal of Clinical Investigation: “Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway.”
The paper authors are: David J. Rozansky, Tonya Cornwall, Arohan R. Subramanya, Shaunessy Rogers, Yong-Feng Yang, Larry L. David, Xiaoman Zhu, Chao-Ling Yang and David H. Ellison (click below for department affiliation).
This paper summary is compiled by Mary Stenzel-Poore, PhD, Associate Dean for Basic Science, and reviewed by Dean Mark Richardson, MD, and Senior Associate Dean/VP for Research Dan Dorsa, PhD. The work described in October’s paper-of-the-month:
• explains a key signaling event in hormonal regulation of Na-Cl reabsorption by the kidney.
• in particular, the study illuminates how the thiazide-sensitive sodium chloride cotransporter (NCC) is regulated by the aldosterone, a hormone responsible for volume and blood pressure control.
• it may provide insights into understanding the pathogenesis of hypertension, including the disorder familial hyperkalemia and hypertension (FHHt).
• reflects a productive research program with clinical/translational importance in the field of renal physiology and blood pressure control.
• was done by a team of OHSU investigators collaborating across the departments of pediatrics, biochemistry and internal medicine.
Summary: A team of OHSU investigators led by David Rozansky of Pediatrics and David Ellison of Medicine have been making substantial inroads into understanding the molecular events that regulate Na-Cl reabsorption in the kidney. This recent paper by Rozansky et al brings together basic and translational scientists to tackle the problem of how the mineralocorticoid hormone, aldosterone, alters renal control of Na-Cl. Aldosterone is known to regulate volume homeostasis and blood pressure by enhancing sodium reabsorption in the kidney.
The effect of aldosterone on sodium reabsorption in the kidney is mediated through regulation of the thiazide-sensitive Na-Cl cotransporter (NCC) and the epithelial sodium channel. While the mechanism for how aldosterone regulates ENaC is well defined, the molecular mechanism for how NCC is regulated by aldosterone remained obscure. Indeed, while physiology studies implicated aldosterone stimulating NCC activity and abundance, the signaling mechanisms responsible for this process were unknown.
Rozansky et al are the first to show key signaling events between the aldosterone sensitive gene, serum and glucocorticoid induced kinase 1 (SGK1) and another kinase, WNK4, which is known to negatively regulate NCC. In a series of elegant in vitro experiments using molecular constructs with mutations in the C-terminal domain of the WNK4 protein, the authors show that SGK1 directly phosphorylates WNK4, thereby blocking WNK4 kinase inhibition of NCC activity. The net effect of aldosterone results in increased NaCl reabsorption via activation of SGK1, which inhibits WNK4 and allows increased NCC activity.
This important link between aldosterone, SGK1, and WNK4 kinase provides molecular support for the phenotypic findings that mutations in the coding region of WNK4 in humans are associated with human high blood pressure in the condition known as familial hyperkalemia and hypertension (FHHt). While numerous questions remain regarding the molecular events that determine how aldosterone balances NaCl reabsorption with other electrolyte derangements, the authors have taken a fundamental step forward supporting a key role for SGK1 as the aldosterone sensitive gene that modulates WNK4 inhibition of NCC activity. Rozansky et al bring a new level of understanding to the molecular events of aldosterone’s actions on the comprehensive signal transduction pathways that regulate NaCl reabsorption in the distal nephron.
David J. Rozansky – MD, Associate Professor, Pediatrics
Tonya Cornwall – Research Associate, Pediatrics
Shaunessy Rogers – Research Assistant, Nephrology & Hypertension
Yong-Feng Yang – Senior Research Associate, Anesthesiology
Larry L. David – PhD, Professor, Biochemistry & Molecular Biology, Ophthalmology
Chao-Ling Yang – MD, Research Assistant Professor, Medicine, Nephrology & Hypertension.
David H. Ellison – MD, Professor, Medicine, Nephrology & Hypertension, Physiology & Pharmacology