Reduction of Stat3 activity attenuates HIV-induced kidney injury.
HIV-1 Nef induces podocyte proliferation and dedifferentiation by activating the Stat3 and MAPK1,2 pathways. Activation of Stat3 also occurs in human kidneys affected by HIV-associated nephropathy (HIVAN), but its contribution to the development of HIVAN is unknown. Here, we generated HIV-1 transgenic mice (Tg26) with either 75% Stat3 activity (Tg26-SA/+) or 25% Stat3 activity (Tg26-SA/-). The kidneys of Tg26-SA/+ mice, but not Tg26-SA/- mice, showed increased Stat3 phosphorylation. The Tg26-SA/+ phenotype was not different from Tg26 mice, but Tg26-SA/- mice developed significantly less proteinuria, glomerulosclerosis, and tubulointerstitial injury. Tg26-SA/+ mice exhibited reduced expression of podocyte differentiation markers and increased expression of VEGF and proliferation markers as compared to Tg26-SA/- mice. Primary podocytes isolated from Tg26-SA/+ mice showed increased Stat3 phosphorylation and reduced expression of podocyte differentiation markers. The tubulointerstitial compartment and isolated tubules of Tg26-SA/+ mice also had increased Stat3 phosphorylation and expression of Stat3 target genes. We confirmed that the expression of the HIV-1 transgene and reduction of Stat3 activity did not affect T and B cell development. In conclusion, Stat3 plays a critical role in the pathogenesis of HIVAN.
Feng
Xiaobei
X
Department of Nephrology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Lu
Ting-Chi
TC
Chuang
Peter Y
PY
Fang
Wei
W
Ratnam
Krishna
K
Xiong
Huabao
H
Ouyang
Xinshou
X
Shen
Yuhong
Y
Levy
David E
DE
Hyink
Deborah
D
Klotman
Mary
M
D'Agati
Vivette
V
Iyengar
Ravi
R
Klotman
Paul E
PE
He
John C
JC
D016263:AIDS-Associated Nephropathy / Q000209:etiology*; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics; D049109:Cell Proliferation; D015497:HIV-1 / Q000235:genetics; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000032:analysis; D050199:Podocytes / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis
D015704:CD4 Antigens; D008840:Microfilament Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C503968:Synpo protein, mouse; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2