Metabolite-GPCR-Salt Transport Determines Diuretic Response

Metabolism-Salt Transport Coupling

Every year, more than 50 million thiazide prescriptions are written in the United States to treat high blood pressure. Although these front-line drugs are often very effective, they don’t always work, and in some patients they may lower blood pressure for a while but then wear off. The reasons for individual variations in the drug response have been an enigma. This program of investigation focuses on solving the mystery with the hopes of developing more effective strategies for treating hypertension


Our recent genomic profiling investigations revealed a likely and surprising culprit, an usual pathway that couples alterations in intermediate metabolism to salt retention.   We discovered that thiazide diuretics or genetic loss of the thiazide-target, NCC, alters proximal tubule metabolism in a way that activates the synthesis and release of α-ketoglutarate (AKG) into the pro-urine. AKG is, then, delivered in the tubular fluid to the distal nephron where it activates its cognate G-protein coupled receptor, OXGR1, and this stimulates a salt reabsorption network (pendrin (Slc26a4)/NDCBE) as a part of a homeostatic response that normally limits urinary salt loss when NCC is inactive.

  

This project assembles a highly collaborative, multidisciplinary team to rigorously test the central tenants of this new intrarenal paracrine-metabolite system in genetically engineered mouse models; to explore the underlying molecular mechanisms; and to translate the basic science to human studies of diuretic resistance. We hope the knowledge gained from these studies will provide insights to personally tailor antihypertensive therapies to individual drug responses.



 

Welling Lab 

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