Reactive oxygen species (ROS) have been demonstrated to contribute to HIV-induced tubular cell injury. We hypothesized that HIV-induced ROS generation may be causing tubular cell injury through downregulation of vitamin D receptor (VDR) and associated downstream effects. In the present study, HIV not only downregulated tubular cell VDR expression but also inflicted DNA injury. On the other hand, EB-1089, a VDR agonist (VD), inhibited both downregulation of VDR and tubular cell DNA injury in the HIV milieu. H(2)O(2) (an O(-) donor) directly downregulated tubular cell VDR, whereas catalase, a free radical scavenger, inhibited HIV-induced downregulation of tubular cell VDR expression. HIV also stimulated the tubular cell renin-angiotensin system (RAS) through downregulation of VDR. Because losartan (an ANG II blolcker) partially inhibited HIV-induced tubular cell ROS generation while ANG II directly stimulated tubular cell ROS generation, it appears that HIV-induced ROS production was partly contributed by the RAS activation. VD not only inhibited HIV-induced RAS activation but also attenuated tubular cell ROS generation. Tubular cells displayed double jeopardy in the HIV milieu induction of double-strand breaks and attenuated DNA repair; additionally, in the HIV milieu, tubular cells exhibited enhanced expression of phospho-p53 and associated downstream signaling. A VDR agonist and an ANG II blocker not only preserved expression of tubular cell DNA repair proteins but also inhibited induction of double-strand breaks. In in vivo studies, renal cortical sections of Tg26 mice displayed attenuated expression of VDR both in podocytes and tubular cells. In addition, renal cortical sections of Tg26 mice displayed enhanced oxidative stress-induced kidney cell DNA damage. These findings indicated that HIV-induced tubular cell downregulation of VDR contributed to the RAS activation and associated tubular cell DNA damage. However, both VD and RAS blockade provided protection against these effects of HIV.

MicroRNAs (miRNAs) play a critical role in multiple biological and metabolic processes. Recent studies suggested that miRNAs are critical in the maintenance of glomerular homeostasis in both physiological and pathological states. However, the role of miRNAs in the pathogenesis of HIV-associated nephropathy (HIVAN) has not been studied. In the present study, we have used a microarray-based approach in combination with real-time PCR to profile the miRNA expression patterns in HIV-1 transgenic mice (Tg26). Our results showed that 13 miRNAs, which belong to 11 miRNA families, were down regulated in HIVAN when compared with control mice. These miRNAs were classified into 20 functional categories. In in vitro studies, we examined the expression of specific miRNAs in HIV-1 transduced human podocytes. Our results showed that HIV-1 down regulated miRNAs expression, specifically of miR-200 and miR-33. These studies suggest that miRNAs contributed to the development of the proliferative phenotype of HIVAN. Further functional analysis of these miRNAs in HIVAN animal model will not only enhance understanding of the pathogenesis but would also lead to the development of therapeutic strategies for HIVAN patients.