Acta Physiologica 2011; Volume 203, Supplement 686
Joint Congress of FEPS and Turkish Society of Physiological Sciences
A DIRECT LINK BETWEEN METABOLISM AND THE TISSUE RENIN-ANGIOTENSIN SYSTEM IN THE COLLECTING DUCT
Abstract number: S5.1
Prokai1 Agnes, Burford1 Jim, Gevorgyan1 Haykanush, Peterfi1 Zalán, Vargas1 Sarah L., Peti Peterdi1 János
1Department of Physiology and Biophysics and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA.
Renin release, the rate-limiting step of RAS is controlled by GPR91, a novel metabolic receptor for succinate. Renin activates a new element of RAS, the (pro)renin receptor [(P)RR]. Furthermore, the renal collecting duct (CD) is the major source of (pro)renin in diabetes. Since the highest renal GPR91 and (P)RR expression was found in the CD, this study investigated whether succinate via GPR91 regulates the local CD RAS including the (P)RR. Western blot analysis of succinate-treated M1 cells (CD cell line) showed a dose-dependent, 22.5-fold elevation in pERK½, pp38, COX2, renin, (P)RR. In WT and GPR91-/- control and STZ-diabetic (DM) mice, CD pERK1/2 (by immunofluorescence) and urinary PGE2 excretion (measured by ELISA) increased 420 fold in DM mice in a GPR91-dependent manner. Medullary (P)RR and (pro)renin protein expression (by immunoblotting) and renin activity in the CD tubular fluid (visualized in vivo using multiphoton microscopy and a fluorogenic renin substrate delivered by renal micropuncture) increased 45 fold in WT DM vs. control mice, which was completely abolished in GPR91-/- DM mice. CD (pro)renin activity was reduced by 40% after aliskiren (direct renin inhibitor) and by 70% following handle region peptide (PRR antagonist) administration. This is the first, direct demonstration of CD renin activity in vivo. Succinate accumulation, and the consequent GPR91-(P)RR signaling are novel (patho)physiological regulatory mechanisms that activate the local RAS in the CD via MAP kinases and COX2, PGE2 release, and increased (pro)renin synthesis. Succinate, GPR91 and (P)RR may be important regulators of the local CD RAS in DM and new therapeutic targets in diabetic nephropathy.
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Acta Physiologica 2011; Volume 203, Supplement 686 :S5.1