title: Sirolimus modulates HIVAN phenotype through inhibition of epithelial mesenchymal transition.
abstract: HIV-associated nephropathy (HIVAN) is characterized by proliferative phenotype in the form of collapsing glomerulopathy and microcystic dilatation of tubules. Recently, epithelial mesenchymal transition (EMT) of renal cells has been demonstrated to contribute to the pathogenesis of proliferative HIVAN phenotype. We hypothesized that sirolimus would modulate HIVAN phenotype by attenuating renal cell EMT. In the present study, we evaluated the effect of sirolimus on the development of renal cell EMT as well as on display of HIVAN phenotype in a mouse model of HIVAN (Tg26). Tg26 mice receiving normal saline (TgNS) showed enhanced proliferation of both glomerular and tubular cells when compared to control mice-receiving normal saline (CNS); on the other hand, Tg26 mice receiving sirolimus (TgS) showed attenuated renal cell proliferation when compared with TgNS. TgNS also showed increased number of α-SMA-, vimentin-, and FSP1-positive cells (glomerular as well as tubular) when compared with CNS; however, TgS showed reduced number of SMA, vimentin, and FSP1+ve renal cells when compared to TgNS. Interestingly, sirolimus preserved renal epithelial cell expression of E-cadherin in TgS. Since sirolimus attenuated renal cell ZEB expression (a repressor of E-cadherin transcription), it appears that sirolimus may be attenuating renal cell EMT by preserving epithelial cell E-cadherin expression.
authors.affiliation: Immunology Center, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, United States.
authors.forename: Anju
authors.initials: A
authors.lastname: Yadav
authors.forename: Dileep
authors.initials: D
authors.lastname: Kumar
authors.forename: Divya
authors.initials: D
authors.lastname: Salhan
authors.forename: Rungwasee
authors.initials: R
authors.lastname: Rattanavich
authors.forename: Subani
authors.initials: S
authors.lastname: Maheshwari
authors.forename: Madhuri
authors.initials: M
authors.lastname: Adabala
authors.forename: Guohua
authors.initials: G
authors.lastname: Ding
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000199:Actins / Q000032:analysis; D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015820:Cadherins / Q000096:biosynthesis; D002135:Calcium-Binding Proteins / Q000032:analysis; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000071999:S100 Calcium-Binding Protein A4; D020123:Sirolimus / Q000627:therapeutic use*; D014157:Transcription Factors / Q000032:analysis; D014746:Vimentin / Q000032:analysis; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D019380:Anti-HIV Agents; D015820:Cadherins; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D000071999:S100 Calcium-Binding Protein A4; D014157:Transcription Factors; D014746:Vimentin; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C077591:S100A4 protein, human; D020123:Sirolimus