Abstract 105: Therapeutic Suppression of Mtorc2 Signaling Reduces Salt-induced Hypertension and Kidney Injury in SS Rats

Abstract

The present study explored the protective effect of mTORC2 inhibition in salt-induced hypertension and kidney injury. We have previously reported that enhanced blood pressure salt-sensitivity with renal chronic interstitial infusion of H 2 O 2 (347 nmol/kg/min) in normotensive Sprague Dawley (SD) rats. In the present study, in vivo experiment was performed in which H 2 O 2 (347 nmol/Kg/min) was chronically infused for 3 days into renal interstitium of unilaterally nephrectomized SD rats. A significant increase of mTORC2 activity (pAKT/AKT) was observed in the renal cortex of SD rats infused with H 2 O 2 compared to saline infused rats. We have recently shown that excess production of H 2 O 2 in the SS rat kidneys is the hallmark of salt-induced hypertension. We hypothesized that mTORC2 in the kidney contributes to the development of salt-induced hypertension in SS rats. Rats were treated with PP242 which is an ATP-competitor inhibitor which inhibits the activities of both mTORC1 and mTORC2 whereas rapamycin specifically inhibits mTORC1. PP242 was administrated daily (i.p., 15 mg/Kg/day) for 21 days to SS rats fed a 4.0% NaCl diet. Remarkably, salt-induced hypertension was significantly reduced in SS rats which averaged 119 ± 2 mmHg in PP242 treated rats (n=7) compared to 168 ± 3 mmHg in vehicle treated rats (n=7). Albuminuria was greatly reduced with urine albumin excretion (mg/day) averaging 32.8 ± 3 in PP242 treated rats compared to 256 ± 37 in vehicle treated rats. PP242 treatment notably resulted in reduced infiltration of T lymphocytes in the kidneys of SS rats fed a 4.0% NaCl diet. CD3 + cells/mm 2 averaging 157.0 ± 40.0 compared to 36.0 ± 11.0 in the renal cortex and 218.0 ± 24.0 compared to 24.0 ± 9.0 in the outer medulla in PP242 versus vehicle treated rats. These data show that mTORC2 is required for the intiation of salt-induced hypertension and therapeutic suppression of this pathway virtually abolished salt-sensitivity blood pressure and kidney injury.