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-α intercalated cells, highlighting the Cl/HCO3- exchanger, pendrin, alpha-ketoglutarate (α-KG) and the α-KG G-Protein Coupled Receptor, OXGR1. Our recently published and preliminary data strongly suggest that paracrine delivery of α-KG stimulates OXGR1 in non-α 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 α-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.