1. Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression
- Author
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Papeta, Natalia, Chan, Ka-Tak, Prakash, Sindhuri, Martino, Jeremiah, Kiryluk, Krzysztof, Ballard, David, Bruggeman, Leslie A., Frankel, Rachelle, Zheng, Zongyu, Klotman, Paul E., Zhao, Hongyu, D'Agati, Vivette D., Lifton, Richard P., and Gharavi, Ali G.
- Subjects
Gene expression -- Research ,Glomerulonephritis -- Risk factors ,Glomerulonephritis -- Diagnosis ,Glomerulonephritis -- Drug therapy ,Glomerulonephritis -- Research ,HIV (Viruses) -- Health aspects ,HIV (Viruses) -- Genetic aspects ,HIV (Viruses) -- Research ,Mice -- Models ,Mice -- Usage - 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., Introduction In the past decade, studies in humans and murine models have implicated defects in the glomerular visceral epithelial cells, the podocytes, as a principal factor in the development of [...]
- Published
- 2009