title: Inhibition of Notch pathway attenuates the progression of human immunodeficiency virus-associated nephropathy.
abstract: The Notch pathway is an evolutionarily conserved signaling cascade that is critical in kidney development and has also been shown to play a pathogenetic role in a variety of kidney diseases. We have previously shown that the Notch signaling pathway is activated in human immunodeficiency virus-associated nephropathy (HIVAN) as well as in a rat model of the disease. In this study, we examined Notch signaling in the well established Tg26 mouse model of HIVAN. Notch signaling components were distinctly upregulated in the kidneys of these mice as well as in immortalized podocytes derived from these mice. Notch1 and Notch4 were upregulated in the Tg26 glomeruli, and Notch4 was also expressed in tubules. Notch ligands Jagged1, Jagged2, Delta-like1, and Delta-like 4 were all upregulated in the tubules of Tg26 mice, but glomeruli showed minimal expression of Notch ligands. To examine a potential pathogenetic role for Notch in HIVAN, Tg26 mice were treated with GSIXX, a gamma secretase inhibitor that blocks Notch signaling. Strikingly, GSIXX treatment resulted in significant improvement in both histological kidney injury scores and renal function. GSIXX-treated Tg26 mice also showed diminished podocyte proliferation and dedifferentiation, cellular hallmarks of the disease. Moreover, GSIXX blocked podocyte proliferation in vitro induced by HIV proteins Nef and Tat. These studies suggest that Notch signaling can promote HIVAN progression and that Notch inhibition may be a viable treatment strategy for HIVAN.
authors: Department of Internal Medicine, The Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA. msharma3@kumc.edu
authors: Madhulika
authors: M
authors: Sharma
authors: Lynn K
authors: LK
authors: Magenheimer
authors: Trisha
authors: T
authors: Home
authors: Karen N
authors: KN
authors: Tamano
authors: Pravin C
authors: PC
authors: Singhal
authors: Deborah P
authors: DP
authors: Hyink
authors: Paul E
authors: PE
authors: Klotman
authors: Gregory B
authors: GB
authors: Vanden Heuvel
authors: Timothy A
authors: TA
authors: Fields
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D054337:Cell Dedifferentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D003984:Dibenzazepines / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008024:Ligands; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D003984:Dibenzazepines; D004151:Dipeptides; D008024:Ligands; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497762:Notch1 protein, mouse; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D051880:Receptors, Notch; C073572:Notch4 protein, mouse; D053829:Amyloid Precursor Protein Secretases
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