Hedgehog pathway plays a vital role in HIV-induced epithelial-mesenchymal transition of podocyte.
HIV-associated nephropathy (HIVAN) is characterized by heavy proteinuria, rapidly progressive renal failure, and distinct morphological features in the kidney. HIV-induced epithelial-mesenchymal transition (EMT) is critically important for the progression of kidney injury. In this study, we tested the role of hedgehog pathway in the HIV-induced EMT and fibrosis of kidney. We used the Tg26 mice, the abundantly used HIVAN mouse model, to investigate the activation of hedgehog pathway by HIV. Western blotting and real time PCR results showed that renal tissue expression of hedgehog pathway related molecules, including hedgehog homologous (Shh, Ihh, Dhh), PTCH, and Gli1, were increased in HIVAN (Tg26) mice; while immunofluorescent staining displayed localization PTCH expression in podocytes. For in vitro studies, we used recombinant sonic hedgehog (Shh) and HIV for their expression by podocytes. Both the methods activated the hedgehog pathway, enhanced the expression of EMT markers, and decreased impermeability. Overexpression of Gli1 by human podocytes also augmented their expression of EMT markers. On the other hand, the blockade of hedgehog pathway with Gant 58, a specific blocker for Gli1-induced transcription, dramatically decreased HIV-induced podocyte EMT and permeability. These results indicate that hedgehog pathway plays an important role in HIV-induced podocyte injury. The present study provides mechanistical insight into a new target for therapeutic strategy.
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra Northwell Medical School, NY, USA. Electronic address: xlan@northwell.edu.
Xiqian
X
Lan
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra Northwell Medical School, NY, USA.
Hongxiu
H
Wen
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra Northwell Medical School, NY, USA.
Kang
K
Cheng
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra Northwell Medical School, NY, USA.
Andrei
A
Plagov
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra Northwell Medical School, NY, USA.
Seyedeh Shadafarin
SS
Marashi Shoshtari
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra Northwell Medical School, NY, USA.
Ashwani
A
Malhotra
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra Northwell Medical School, NY, USA. Electronic address: psinghal@northwell.edu.
Pravin C
PC
Singhal
D000818:Animals; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006678:HIV; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D050199:Podocytes / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D011725:Pyridines / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
C000593413:GANT58; D053823:Hedgehog Proteins; D011725:Pyridines; D013876:Thiophenes
Epithelial-mesenchymal transition; HIV-associated nephropathy; Hedgehog pathway; Podocyte