Thiazides are one of the most cost-effective and medically beneficial first line antihypertensive agents. However, they don?t work for everyone, and in some patients they may lower blood pressure for a while but then wear off. The mechanisms responsible for thiazide resistance have been mysterious, until recently. Our recent systems-biology investigations revealed a salt-transport process is activated by a novel mechanism to limit urinary salt wasting when NCC, the thiazide target, is inhibited or hypokalemic intravascular volume depletion occurs. We discovered that a salt reabsorption pathway is created by the coordinate induction of a multi-gene transport system in non-? intercalated cells, highlighting the Cl/HCO3- exchanger, pendrin, alpha-ketoglutarate (?-KG) and the ?-KG G-Protein Coupled Receptor, OXGR1. Our recently published and preliminary data strongly suggest that paracrine delivery of ?-KG stimulates OXGR1 in non-? cells and this activates pendrin, stimulates salt reabsorption, and potentially lowers the diuretic response. Here, we have assembled a highly collaborative, multidisciplinary team to rigorously test the central tenants of the ?- KG /OXGR1/pendrin hypothesis (Aim 1), explore the underlying molecular mechanism(s) linking OXGR1 to pendrin activation (Aim 2), elucidate the physiological stimuli and consequences of the Renal ?-KG/OxGR1 Paracrine system (Aim 3), building on our recent discoveries. We expect these investigations will have a major impact on understanding how the kidney controls salt balance in health and disease, in ways that illuminate the central underpinnings of the variable diuretic response. Ultimately, these studies will provide new information and diagnostic tools that lead to the better treatment of hypertension.
Essential hypertension is a major threat to public health, affecting over a billion people on the planet and contributing to chronic kidney disease and cardiovascular disease in excess of five million people annually. The basis of essential hypertension is largely unknown, and current treatment strategies are suboptimal. This program of investigation will provide a new understanding of the adaptive kidney processes that limit the effectiveness of a widely used class of antihypertensive drugs, the thiazide diuretics, and translate this knowledge to drug discovery. Specifically, it examines how a salt gaining pathway is activated by the alpha-ketoglutarate receptor, OXGR1, in intercalated cells of the kidney when the thiazide- sensitive salt transport is inhibited, or when hypokalemic intravascular volume contraction occurs, as is commonly observed with vomiting or diarrhea. We expect these investigations will have a major impact on understanding how the kidney controls salt balance in health and disease, in ways that illuminate the central underpinnings of the variable diuretic response. Ultimately, these studies will provide new information and diagnostic tools that lead to the better treatment of hypertension.
| Lazo-Fernandez, Yoskaly; Welling, Paul A; Wall, Susan M (2018) ?-Ketoglutarate stimulates pendrin-dependent Cl- absorption in the mouse CCD through protein kinase C. Am J Physiol Renal Physiol 315:F7-F15 |
| Grimm, P Richard; Coleman, Richard; Delpire, Eric et al. (2017) Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules. J Am Soc Nephrol 28:2597-2606 |
