P100 ALPHA KETOGLUTARATE RECEPTOR 1 REGULATES THE EXPRESSION OF THE (PRO)RENIN RECEPTOR IN MEDULLARY RENAL TISSUES, MODULATES SODIUM EXCRETION AND ATTENUATES TWO-KIDNEY, ONE-CLIP GOLDBLATT HYPERTENSION IN MICE

Background: The two-kidney, one-clip (2K1C) Goldblatt model elicits a reduction of renal blood flow (RBF) in the clipped kidney (CK). The reduced RBF and oxygen bio ability causes the accumulation of the intermediary of the tricarboxylic cycle, α-ketoglutarate, which activates the oxoglutarate receptor-1 (OXGR1). In the kidney, the OXGR1 is abundantly expressed in intercalated cells (IC) of the collecting duct (CD), which may contribute to Na+ transport and electrolyte balance. The (pro)renin receptor (PRR), a member of the renin-angiotensin-aldosterone system is a key regulator of Na+ reabsorption, and blood pressure (BP) and is also expressed in IC. PRR is upregulated in 2K1C. Here, we tested the hypothesis that reduction of RBF in the CK leads to OXGR1-dependent PRR upregulation in the CD and alterations of Na+ balance and BP in 2K1C mice. Methods: To determine the role of OXGR1 in regulating PRR in the CDs during renovascular hypertension, we used 2K1C Goldblatt surgery (clip= 0.13 mm internal gap) in two groups of male mice: 1) Oxgr1-/- knockout (n=6) mice; and 2) mice treated with Montelukast (OXGR1 antagonist; 5 mg/Kg/day, n=6). WT and sham-operated mice were used as controls. Results: 2K1C mice showed increased systolic BP (SBP) (108 ± 11 vs. control 82 ± 5 mmHg, p<0.01) and a lower natriuretic response after the saline challenge test. The CK showed augmented levels of α-ketoglutarate, erythropoietin mRNA levels, PRR (mRNA and protein abundances) in the renal medulla. Non-CK showed PRR upregulation in the CDs. However, the CK of Oxgr1-/- knockout mice, and from those subjected to OXGR1 antagonism, elicited impaired PRR upregulation, attenuated SBP (Oxgr1-/- 2K1C: 90 ± 8 mmHg, p=non-significant vs. control; Montelukast 2K1C: 95 ± 3 mmHg, p<0.05 vs. control) and better natriuretic responses. Conclusion: In 2K1C mice, the effect of reduced RBF on the OXGR1-dependent PRR upregulation in the CK may contribute to the anti-natriuretic and increased SBP responses.