Reduction of Stat3 activity attenuates HIV-induced kidney injury.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Feng, X; Lu, T-C; Chuang, PY; Fang, W; Ratnam, K; Xiong, H; Ouyang, X; Shen, Y; Levy, DE; Hyink, D; Klotman, M; D'Agati, V; Iyengar, R; Klotman, PE; He, JC
Published Date
- October 2009
Published In
Volume / Issue
- 20 / 10
Start / End Page
- 2138 - 2146
PubMed ID
- 19608706
Pubmed Central ID
- PMC2754106
Electronic International Standard Serial Number (EISSN)
- 1533-3450
Digital Object Identifier (DOI)
- 10.1681/ASN.2008080879
Language
- eng
Conference Location
- United States