title: HIVAN phenotype: consequence of epithelial mesenchymal transdifferentiation.
abstract: Human immunodeficiency virus (HIV)-1-associated nephropathy (HIVAN) is characterized by proliferation of glomerular and tubular epithelial cells. We studied the role of epithelial mesenchymal transdifferentiation (EMT) in the development of HIVAN phenotype. Renal cortical sections from six FVB/N (control) and six Tg26 (HIVAN) mice were immunolabeled for PCNA, alpha-smooth muscle actin (alpha-SMA), fibroblast-specific protein-1 (FSP1), CD3, and F4/80. Since periglomerular cells (PGCs) and peritubular cells (PTCs) did not show any labeling for CD3 and F4/80 but showed labeling for alpha-SMA or FSP1, it appears that these were myofibroblasts that migrated from either glomerular or tubular sites, respectively. Occurrence of EMT was also supported by diminished expression of E-cadherin by renal epithelial cells in Tg26 mice. Interestingly, Tg26 mice also showed enhanced renal tissue expression of ZEB2; henceforth, it appears that transcription of molecules required for maintenance of de novo renal epithelial cell phenotype was suppressed. To evaluate the role of ANG II, Tg26 mice in groups of three were administered either normal saline or telmisartan (an AT1 receptor blocker) for 2 wk, followed by evaluation for renal cell EMT. Renal cortical section of Tg26 mice showed a sevenfold increase (P < 0.001) in parietal epithelial cell (PEC)-PGC and a threefold increase (P < 0.01) in tubular cell (TC)-PTC proliferation (PCNA-positive cells). Similarly, both PECs-PGCs and TCs-PTCs in Tg26 mice showed enhanced expression of alpha-SMA and FSP1. Both PECs and podocytes contributed to the glomerular proliferative phenotype, but the contribution of PECs was much greater. Telmisartan-receiving Tg26 mice (TRM) showed attenuated number of proliferating PECs-PGCs and TCs-PTCs compared with saline-receiving Tg26 mice (SRM). Similarly, TRM showed diminished expression of alpha-SMA and FSP1 by both PECs-PGCs and TCs-PTCs compared with SRM. We conclude that EMT contributes to the manifestation of the proliferative phenotype in HIVAN mice.
authors.affiliation: Immunonlogy Center, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
authors.forename: Anju
authors.initials: A
authors.lastname: Yadav
authors.forename: Sridevi
authors.initials: S
authors.lastname: Vallabu
authors.forename: Dileep
authors.initials: D
authors.lastname: Kumar
authors.forename: Guohua
authors.initials: G
authors.lastname: Ding
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Charney
authors.forename: Praveen N
authors.initials: PN
authors.lastname: Chander
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage; D001565:Benzoates / Q000008:administration & dosage; D015820:Cadherins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D055104:Infusions, Subcutaneous; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D050199:Podocytes / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D013601:T-Lymphocytes / Q000473:pathology; D000077333:Telmisartan
chemical_list: D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D015820:Cadherins; D002135:Calcium-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D000804:Angiotensin II; D000077333:Telmisartan