HIV-1 upregulates VEGF in podocytes.
HIV-associated nephropathy (HIVAN) is characterized by collapsing FSGS. Because transgenic mice with podocyte-specific overexpression of the vascular endothelial growth factor 164 (VEGF164) isoform also develop collapsing FSGS, we sought to determine whether VEGF plays a role in HIVAN. Compared with controls, immunohistochemistry revealed that kidneys from HIV-1-transgenic mice (Tg26) and from patients with HIVAN had greater expression of both VEGF and its transcriptional regulator, hypoxia-inducible factor 2alpha (HIF-2alpha). Similarly, mRNA and protein levels of VEGF and HIF-2alpha were increased in HIV-infected podocytes in vitro, and this transcriptional upregulation was found to be stimulated by the HIV viral protein Nef in a Src kinase-and Stat3-dependent manner. HIV-1 also upregulated VEGFR2 and its co-receptor neuropilin-1 and suppressed the expression of semaphorin 3a in the podocyte. Exogenous VEGF stimulated proliferation and de-differentiation of podocytes, which are features of collapsing FSGS, and VEGFR2 neutralizing antibodies reversed these features in podocytes infected with HIV-1 or isolated from Tg26 mice. In conclusion, HIV-1 induces VEGF and VEGFR2 expression in podocytes, and this may be a critical step in the pathogenesis of HIVAN.
Korgaonkar
Sonal Navin
SN
Department of , New York, Mount Sinai School of Medicine, New York, USA.
Feng
Xiaobei
X
Ross
Michael D
MD
Lu
Ting-chi
TC
D'Agati
Vivette
V
Iyengar
Ravi
R
Klotman
Paul E
PE
He
John Cijiang
JC
D016263:AIDS-Associated Nephropathy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D002461:Cell Line, Transformed; D015967:Gene Expression Regulation, Viral; D015497:HIV-1; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000166:cytology / Q000502:physiology* / Q000821:virology*; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1; C467484:VEGFA protein, human; C467480:vascular endothelial growth factor A, mouse