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

J Clin Invest. 2009 May;119(5):1178-88. doi: 10.1172/JCI37131. Epub 2009 Apr 20.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS-Associated Nephropathy / etiology
  • AIDS-Associated Nephropathy / genetics*
  • Animals
  • Chromosomes / genetics
  • Crosses, Genetic
  • Gene Expression / genetics
  • Gene Expression Regulation / genetics*
  • Genetic Linkage / genetics
  • Genetic Predisposition to Disease / genetics*
  • HIV-1 / genetics
  • Intracellular Signaling Peptides and Proteins / genetics
  • Kidney / metabolism
  • Kidney / pathology
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Microfilament Proteins / genetics
  • Nonmuscle Myosin Type IIA / genetics
  • Phosphoinositide Phospholipase C / genetics
  • Phylogeny
  • Podocytes / metabolism*
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Kirrel1 protein, mouse
  • Membrane Proteins
  • Microfilament Proteins
  • Myh9 protein, mouse
  • NPHS2 protein
  • Synpo protein, mouse
  • nephrin
  • Phosphoinositide Phospholipase C
  • phospholipase C epsilon
  • Nonmuscle Myosin Type IIA