ARB protects podocytes from HIV-1 nephropathy independently of podocyte AT1

BACKGROUND: Angiotensin I-converting enzyme inhibitors and angiotensin receptor blockers protect podocytes more effectively than other anti-hypertensive drugs. Transgenic rats overexpressing angiotensin II Type 1 (AT1) receptor selectively in podocytes have been shown to develop glomerulosclerosis. The prevailing hypothesis is that angiotensin II has a capacity of directly acting on the AT1 receptor of podocytes to induce injury. We therefore investigated the mechanism of reno-protective effect of AT1 receptor in a mouse model of HIV-1 nephropathy. METHODS: We generated transgenic mice carrying the HIV-1 gene (control/HIV-1) or both HIV-1 gene and podocyte-selectively nullified AT1 gene (AT1KO/HIV-1). In these mice, we measured urinary protein or albumin excretion and performed histological analysis. RESULTS: At 8 months of age, AT1KO/HIV-1 (n = 13) and control/HIV-1 (n = 15) mice were statistically indistinguishable with respect to urinary albumin/creatinine ratio (median 2.5 versus 9.1 mg/mg), glomerulosclerosis (median 0.63 versus 0.45 on 0-4 scale) and downregulation of nephrin (median 6.90 versus 7.02 on 0-8 scale). In contrast to the observed lack of effect of podocyte-specific AT1KO, systemic AT1 inhibition with AT1 blocker (ARB) significantly attenuated proteinuria and glomerulosclerosis in HIV-1 mice. CONCLUSION: These results indicate that the protective effect of ARB is mediated through its receptors on cells other than podocytes, such as efferent arteriolar smooth muscle cells.