Intrarenal angiotensin II mediated ROCK1 activation promotes hypertension during chronic acidotic conditions

Abstract

The newly reported model of experimental hypertension delineates the scope of chronic metabolic acidosis as a cause of hypertension. The observed mechanism to promote hypertension during the acidotic conditions are regulated by intrarenal angiotensin II (Ang II) and oxidative stress functioning synergistically. The present study investigates the role of Rho Kinase (ROCK1) in mediating intrarenal activation of Ang II and the renal cell oxidative state during the observed acidosis elicited hypertension. Chronic metabolic acidosis (CMA) was induced in male Sprague Dawley rats (100-150 g) by providing a weak acid solution of 0.28 M ammonium chloride (NH4CL) in tap water for 8 weeks. To confirm the rats were acidotic, blood pH was measured, while blood pressure was monitored weekly using tail-cuff. Rats were divided into five groups: Control (vehicle treated), CMA (acidotic), CMA+spironolactone (to evaluate aldosterone effect), CMA+captopril (to evaluate Ang II effect), and CMA+tempol (to evaluate free radical effect). Microdialysis probes were implanted to the rat’s renal compartments in each group to collect the interstitial fluid. ELISA was performed to quantifying the ROCK1 in all the dialysate samples. In the CMA rats, sustained elevation in the mean arterial pressure (MAP), associated with the significant decrease in blood pH was observed compared to the Control group over the 8 weeks. A significant decrease in MAP was observed in CMA rats treated with captopril and tempol, whereas spironolactone treatment caused no decrease in MAP as compared to the CMA group. The interstitial ROCK1 was significantly increased in the CMA group vs control but decreased significantly in the CMA+captopril vs CMA and CMA+tempol vs CMA groups respectively. This suggested the intrarenal ROCK1 is regulating the Ang II and ROS generation in the renal compartment. Overall, this supports our hypothesis that ROCK pathway and its interaction with intrarenal Ang II and oxidative stress plays a pivotal role in the pathogenesis of acidosis promoted hypertension. VCOM Departmental funding This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.