Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression

Abstract

Multiple studies have linked podocyte gene variants to diverse sporadic nephropathies, including HIV-1-associated nephropathy (HIVAN). We previously used linkage analysis to identify a major HIVAN susceptibility locus in mouse, HIVAN1. We performed expression quantitative trait locus (eQTL) analysis of podocyte genes in HIV-1 transgenic mice to gain further insight into genetic susceptibility to HIVAN. In 2 independent crosses, we found that transcript levels of the podocyte gene nephrosis 2 homolog (Nphs2), were heritable and controlled by an ancestral cis-eQTL that conferred a 3-fold variation in expression and produced reactive changes in other podocyte genes. In addition, Nphs2 expression was controlled by 2 trans-eQTLs that localized to the nephropathy susceptibility intervals HIVAN1 and HIVAN2. Transregulation of podocyte genes was observed in the absence of HIV-1 or glomerulosclerosis, indicating that nephropathy susceptibility alleles induce latent perturbations in the podocyte expression network. Presence of the HIV-1 transgene interfered with transregulation, demonstrating effects of gene-environment interactions on disease. These data demonstrate that transcript levels of Nphs2 and related podocyte-expressed genes are networked and suggest that the genetic lesions introduced by HIVAN susceptibility alleles perturb this regulatory pathway and transcriptional responses to HIV-1, increasing susceptibility to nephropathy.

Comparison of Risk Factors and Outcomes in HIV Immune Complex Kidney Disease and HIV-Associated Nephropathy

“…The importance of HIV RNA in the development of HIVICK has been suggested by the failure to generate this entity in experimental models. Contrary to HIVAN, in which many HIV-1 transgenic models exhibit the clinical and pathologic features of HIVAN, none of these animal models exhibit features of HIVICK (28,29). This observation suggests that viral replication or immune responses to viral proteins may be essential to trigger HIVICK (30).…”

<b>Genetic background-dependent diversity in renal failure caused by the tensin2 gene deficiency in the </b><b>mouse </b>

“…Elucidation of the reasons for the distinct difference in susceptibility to Tns2-deficiency among renal disease due to podocyte-specific knockout of tetraspanin CD151, whereas B6 strain is generally resistant to experimental glomerular disease, including HIV-associated nephropathy and adriamycininduced nephropathy (16)(17)(18). Like Cd151, Tns2 interacts with integrins and its deficiency leads to alterations in the podocyte foot processes (16)(17)(18).…”

Identification of the Nephropathy-Susceptibility Locus HIVAN4

“…In this regard and similar to humans, genetic susceptibility has a profound effect on the development of nephropathy in the HIV-1 transgenic mouse model: the FVB/NJ strain is very susceptible, but F1 hybrids with BALB/cJ, C57BL/6J and CAST/EiJ are protected. 17,18 Taking advantage of this strain dependence, we previously generated mapping cohorts between TgFVB and two counterstrains (C57BL/6J and CAST/EiJ strains), leading to identification of nephropathy quantitative trait loci (QTLs) on chromosomes 3, 13, and 4 (HIVAN1, HIVAN2, and HIVAN3 loci, respectively). 17,18 Further examination of these loci with expression QTL analysis (expression profiling combined with linkage analysis) showed that the HIVAN1 and HIVAN2 loci regulate expression of Nphs2 (encoding Podocin) and several other podocyte-expressed genes.…”

“…17,18 Taking advantage of this strain dependence, we previously generated mapping cohorts between TgFVB and two counterstrains (C57BL/6J and CAST/EiJ strains), leading to identification of nephropathy quantitative trait loci (QTLs) on chromosomes 3, 13, and 4 (HIVAN1, HIVAN2, and HIVAN3 loci, respectively). 17,18 Further examination of these loci with expression QTL analysis (expression profiling combined with linkage analysis) showed that the HIVAN1 and HIVAN2 loci regulate expression of Nphs2 (encoding Podocin) and several other podocyte-expressed genes. 18 These data indicated the HIVAN1 and HIVAN2 susceptibility genes belong to a common regulatory pathway, and they likely introduce genetic lesions in an expression network involving multiple human nephropathy genes.…”

“…17,18 Further examination of these loci with expression QTL analysis (expression profiling combined with linkage analysis) showed that the HIVAN1 and HIVAN2 loci regulate expression of Nphs2 (encoding Podocin) and several other podocyte-expressed genes. 18 These data indicated the HIVAN1 and HIVAN2 susceptibility genes belong to a common regulatory pathway, and they likely introduce genetic lesions in an expression network involving multiple human nephropathy genes.…”