title: Hyperglycemia enhances kidney cell injury in HIVAN through down-regulation of vitamin D receptors.
abstract: In the present study, we evaluated the effect of short term hyperglycemia on renal lesions in a mouse model (Tg26) of HIV-associated nephropathy (HIVAN). Control and Tg26 mice in groups (n=6) were administered either normal saline (FVBN or Tg) or streptozotocin (FVBN+STZ or Tg26+STZ). After two weeks, biomarkers were collected and kidneys were harvested. FVBN+ STZ and Tg26+STZ displayed elevated serum glucose levels when compared to FVBN and Tg26 respectively. Tg26+STZ displayed elevated (P<0.05) blood urea nitrogen (BUN) levels (P<0.05) and enhanced (P<0.01) proteinuria when compared to Tg26. Tg26+STZ displayed enhanced (P<0.001) number of sclerotic glomeruli and microcysts vs. Tg26. Renal tissues of Tg26 displayed down regulation of vitamin D receptor (VDR) expression and enhanced Ang II production when compared to FVBN mice. Hyperglycemia exacerbated down regulation of VDR and production of Ang II in FVBN and Tg mice. Hyperglycemia increased kidney cell reactive oxygen species (ROS) production and oxidative DNA damage in both FVBN and Tg26 mice. In in vitro studies, HIV down regulated podocyte VDR expression and also enhanced renin angiotensin system activation. In addition, both glucose and HIV stimulated kidney cell ROS generation and DNA damage and compromised DNA repair; however, tempol (superoxide dismutase mimetic), losartan (Ang II blocker) and EB1089 (VDR agonist) provided protection against DNA damaging effects of glucose and HIV. These findings indicated that glucose activated the RAS and inflicted oxidative stress-mediated DNA damage via down regulation of kidney cell VDR expression in HIV milieu both in vivo and in vitro.
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
authors.forename: Partab
authors.initials: P
authors.lastname: Rai
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
authors.forename: Tejinder
authors.initials: T
authors.lastname: Singh
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
authors.forename: Rivka
authors.initials: R
authors.lastname: Lederman
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
authors.forename: Amrita
authors.initials: A
authors.lastname: Chawla
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
authors.forename: Dileep
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
authors.forename: Kang
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
authors.forename: Gautam
authors.initials: G
authors.lastname: Valecha
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK. Electronic address: psinghal@nshs.edu.
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000378:metabolism / Q000473:pathology*; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D057809:HEK293 Cells; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin / Q000633:toxicity; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D018167:Receptors, Calcitriol; D054301:gag Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus; D000808:Angiotensinogen; D013311:Streptozocin; D005947:Glucose
keywords: 8-OHdG; DNA damage; Kidney injury; Oxidative stress