HIV-Associated Nephropathy

• DOI: 10.2353/ajpath.2010.100131
• Publication Date: 2010-06-26T00:40:53Z
• Authors: Dileep Kumar; Sridevi Konkimalla; Anju Yadav; Kavithalakshmi Sa...; Balakuntalam S. K...; Praveen N. Chander; Pravin C. Singhal
• Keywords: Male; Vascular Endothelial Growth Factor A; 0303 health sciences; TOR Serine-Threonine Kinases; Kidney Glomerulus; Ribosomal Protein S6 Kinases, 70-kDa; Mice, Transgenic; Hypoxia-Inducible Factor 1, alpha Subunit; 3. Good health; Mice; 03 medical and health sciences; Kidney Tubules; Phenotype; Animals; Humans; AIDS-Associated Nephropathy; Signal Transduction

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-alpha and also displayed increased expression of vascular endothelial growth factor; on the other hand, rapamycin inhibited RT-Tg expression of both hypoxia-inducible factor-alpha 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.