HIV-1 Genes vpr and nef Synergistically Damage Podocytes, Leading to Glomerulosclerosis

Abstract

This study aimed to identify the causative gene for HIV-1 associated nephropathy, a paradigmatic podocytopathy. A previous study demonstrated that transgenic expression of nonstructural HIV-1 genes selectively in podocytes in mice with FVB/N genetic background resulted in podocyte injury and glomerulosclerosis. In this study, transgenic mice that expressed individual HIV-1 genes in podocytes were generated. Five of six transgenic mice that expressed vpr developed podocyte damage and glomerulosclerosis. Analysis of an established vpr transgenic line revealed that transgenic mice on FVB/N but not on C57BL/6 genetic background developed podocyte injury by 8 wk of age, with later glomerulosclerosis. Four of 11 transgenic mice that expressed nef also developed podocyte injury. One transgenic line was established from the nef founder mouse with the mildest phenotype. Transgenic mice in this line developed mesangial expansion at 3 wk of age and mild focal podocyte damage at 10 wk of age. Mating with FVB/N mice did not augment nephropathy. None of the transgenic mice that expressed vif, tat, rev, or vpu in podocytes, even with the FVB/N genetic background, developed podocyte injury. For testing effects of simultaneous expression of vpr and nef, these two lines were mated. All nef:vpr double-transgenic mice showed severe podocyte injury and glomerulosclerosis by 4 wk of age. In contrast, all vpr or nef single-transgenic mice in the same litter uniformly showed no or much milder podocyte injury. These findings indicate that vpr and nef each can induce podocyte injury with a prominent synergistic interaction.

Functional genetic variation in aminopeptidase A (ENPEP): Lack of clear association with focal and segmental glomerulosclerosis (FSGS)

“…Genetic insults include mutations in genes that encode major proteins of the podocyte slit diaphragm and cytoskeleton such as the NPHS1 (nephrin), NPHS2 (podocin), ACTN4 (α-actinin-4) and TRPC6 (transient receptor potential-canonical 6 ion channel) genes (Boute, et al, 2000;Kaplan, et al, 2000;Kestila, et al, 1998;Reiser, et al, 2005;Winn, et al, 2005). Environmental causes such as the human immunodeficiency virus-1 (HIV) (Barisoni, et al, 1999;Kaufman, et al, 2007;Ross, et al, 2005;Schwartz, et al, 2001;Zuo, et al, 2006), and glucose-induced injury (via type 1 and type 2 diabetes) (Mogensen, 1976;Mogensen, 1984;Nosadini and Tonolo, 2003) have been well described, while physiological triggers include (but are not be limited to) elevated blood pressure (Forbes, et al, 2002;Ichihara, et al, 2006;Kretzler, et al, 1994;Nagase, et al, 2006;Szokol, et al, 1979).…”

HIV-1 Upregulates VEGF in Podocytes

“…23 In contrast, recent studies have shown that podocyte-specific expression of Nef in transgenic mice on the FVB/N genetic background develop significant GS. 24 In these mice, podocytes exhibit a loss of differentiation markers in the absence of proliferation. Thus, the exact combination of factors that lead to podocyte proliferation in vivo remains unclear.…”

In-Depth Review of Human Immunodeficiency Virus-Associated Nephropathy

“…It is involved in de-differentiation and proliferation of podocytes, which normally are terminally differentiated (Husain et al, 2002;He et al, 2004;Zhong et al, 2005;Zuo et al, 2006).…”