Deletion of podocyte STAT3 mitigates the entire spectrum of HIV-1-associated nephropathy.
OBJECTIVE
HIV-1 gene expression in kidney epithelial cells is thought to be responsible for the pathogenesis of HIV-1-associated nephropathy (HIVAN). Signal transducer and activator of transcription (STAT) 3 signaling is activated in podocytes of patients with HIVAN and drives the dedifferentiation and proliferation of podocytes in culture. We confirm here that deletion of podocyte STAT3 is sufficient to mitigate the glomerular as well as tubulointerstitial findings of HIVAN.


METHODS
To demonstrate the functional role of podocyte STAT3 in the pathogenesis of HIVAN we compared the development of HIVAN in Tg26 HIV-transgenic mice with and without deletion of STAT3 in the podocyte.


RESULTS
Tg26 mice with podocyte-specific STAT3 deletion developed significantly less weight loss, albuminuria, and renal function impairment compared to Tg26 mice without STAT3 deletion. Tg26 mice with podocyte STAT3 deletion also had significantly less glomerular collapse, sclerosis, epithelial cell hyperplasia, podocyte dedifferentiation, and proinflammatory STAT3 target gene expression; and tubulointerstitial changes of HIVAN, including tubular atrophy, degeneration, apoptosis, and lymphocyte infiltration, were also significantly reduced compared to Tg26 mice without STAT3 deletion.


CONCLUSIONS
Development of glomerular as well as tubulointerstitial injuries in the Tg26 HIVAN model is dependent on podocyte STAT3 expression. Inhibition of STAT3 could be a potential adjunctive therapy for the treatment of HIVAN.
Division of Nephrology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Leyi
L
Gu
Yan
Y
Dai
Jin
J
Xu
Sandeep
S
Mallipattu
Lewis
L
Kaufman
Paul E
PE
Klotman
John C
JC
He
Peter Y
PY
Chuang
D016263:AIDS-Associated Nephropathy / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D000419:Albuminuria; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000150:complications / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012598:Sclerosis; D015398:Signal Transduction / Q000235:genetics; D015431:Weight Loss
D035683:MicroRNAs; D050796:STAT3 Transcription Factor