Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression.
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.
Papeta
Natalia
N
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Chan
Ka-Tak
KT
Prakash
Sindhuri
S
Martino
Jeremiah
J
Kiryluk
Krzysztof
K
Ballard
David
D
Bruggeman
Leslie A
LA
Frankel
Rachelle
R
Zheng
Zongyu
Z
Klotman
Paul E
PE
Zhao
Hongyu
H
D'Agati
Vivette D
VD
Lifton
Richard P
RP
Gharavi
Ali G
AG
D016263:AIDS-Associated Nephropathy / Q000209:etiology / Q000235:genetics*; D000818:Animals; D002875:Chromosomes / Q000235:genetics; D003433:Crosses, Genetic; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D018995:Myosin Heavy Chains; D024507:Nonmuscle Myosin Type IIA / Q000235:genetics; D054801:Phosphoinositide Phospholipase C / Q000235:genetics; D010802:Phylogeny; D050199:Podocytes / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; C486606:Kirrel1 protein, mouse; D008565:Membrane Proteins; D008840:Microfilament Proteins; C525088:Myh9 protein, mouse; C407223:NPHS2 protein; C503968:Synpo protein, mouse; C113267:nephrin; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains