HIV-associated nephropathy: Role of mammalian target of rapamycin pathway

Dileep Kumar, Sridevi Konkimalla, Anju Yadav, Kavithalakshmi Sataranatarajan, Balakuntalam S. Kasinath, Praveen N. Chander, Pravin C. Singhal

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Both glomerular and tubular lesions are characterized by a proliferative phenotype in HIV-associated nephropathy. We hypothesized that mammalian target of rapamycin (mTOR) contributes to the development of the HIVAN phenotype. Both glomerular and tubular epithelial cells showed enhanced expression of phospho (p)-mTOR in HIV-1 transgenic mice (Tgs). In addition, renal tissues of transgenic mice (RT-Tg) showed enhanced phosphorylation of p70S6 kinase and an associated diminished phosphorylation of eEF2. Moreover, RT-Tgs showed enhanced phosphorylation of 4EBP1 and eIF4B; these findings indicated activation of the mTOR pathway in RT-Tgs. To test our hypothesis, age-and sex-matched control mice and Tgs were administered either saline or rapamycin (an inhibitor of the mTOR pathway) for 4 weeks. Tgs receiving rapamycin not only showed inhibition of the mTOR-associated downstream signaling but also displayed attenuated renal lesions. RT-Tgs showed enhanced expression of hypoxia-inducible factor-α and also displayed increased expression of vascular endothelial growth factor; on the other hand, rapamycin inhibited RT-Tg expression of both hypoxia-inducible factor-α and vascular endothelial growth factor. We conclude that the mTOR pathway contributes to the HIVAN phenotype and that inhibition of the mTOR pathway can be used as a therapeutic strategy to alter the course of HIVAN.

Original languageEnglish (US)
Pages (from-to)813-821
Number of pages9
JournalAmerican Journal of Pathology
Volume177
Issue number2
DOIs
StatePublished - Aug 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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