Renin Angioensin Aldosterone System in Drub Abuse and HIV-associated Nephropathy

Feinstein Institute For Medical Research, Manhasset NY

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Abstract

DESCRIPTION (provided by applicant): The renin- Angiotensin- Aldosterone System (RAAS) has been demonstrated to play an important role in the development and progression of renal lesions in both human and animal models of focal glomerulosclerosis (FGS). Interestingly, pharmaceutical agents which modulate the effects of Ang II have been the only ones investigated and proven to alter the course of HIV-associated nephropathy (HIVAN). Since inhibition of two other components of RAAS- eplerenone (a selective inhibitor of aldosterone) and aliskiren (a selective renin inhibitor) have also been reported to modulate the progression of renal lesions in non-HIVAN models of FGS, we hypothesize that use of these agents either alone or in combination with ACE (angiotensin I converting enzyme) inhibitors/AT1 receptor blockers will not only attenuate or prevent HIV-1-induced injury but also delay or slow down the progression of HIVAN. In preliminary studies, we observed that renal cells in mice transgenic HIV-1 genes (HIVAN mice, Tg26) not only showed activation of the mTOR pathway but also displayed enhanced epithelial mesenchymal transdifferentiation (EMT). Interestingly, aliskiren not only inhibited the activation of mTOR pathway as well as renal cell EMT but also attenuated HIVAN phenotype. Moreover, renal tissue of HIVAN (Tg26) mice showed six-fold increase in renin mRNA expression. These findings indicate that the activation of EMT and mTOR pathways in renal cells may be mediated either directly through renin or its downstream effector molecules such as Ang II. Since the activation of the RAAS (host factor) and or African descent (genetic factor) alone has not been shown to manifest into HIVAN phenotype in other renal disease models, it appears that manifestation of HIVAN phenotype requires specific environmental factors, such as renal cell expression of HIV-1 genes. Although, we can not change the ancestry but we can modulate the environmental (HIV-1 infection) and host factors. Based on our preliminary data, we hypothesize that modulation of RAAS by its selective inhibitors will not only prevent or attenuate HIV-1- induced renal injury but also delay or slow down the progression of HIVAN.