title: ARB protects podocytes from HIV-1 nephropathy independently of podocyte AT1.
abstract: BACKGROUND
  Angiotensin I-converting enzyme inhibitors and angiotensin receptor blockers protect podocytes more effectively than other anti-hypertensive drugs. Transgenic rats overexpressing angiotensin II Type 1 (AT1) receptor selectively in podocytes have been shown to develop glomerulosclerosis. The prevailing hypothesis is that angiotensin II has a capacity of directly acting on the AT1 receptor of podocytes to induce injury. We therefore investigated the mechanism of reno-protective effect of AT1 receptor in a mouse model of HIV-1 nephropathy.
  
  
  METHODS
  We generated transgenic mice carrying the HIV-1 gene (control/HIV-1) or both HIV-1 gene and podocyte-selectively nullified AT1 gene (AT1KO/HIV-1). In these mice, we measured urinary protein or albumin excretion and performed histological analysis.
  
  
  RESULTS
  At 8 months of age, AT1KO/HIV-1 (n = 13) and control/HIV-1 (n = 15) mice were statistically indistinguishable with respect to urinary albumin/creatinine ratio (median 2.5 versus 9.1 mg/mg), glomerulosclerosis (median 0.63 versus 0.45 on 0-4 scale) and downregulation of nephrin (median 6.90 versus 7.02 on 0-8 scale). In contrast to the observed lack of effect of podocyte-specific AT1KO, systemic AT1 inhibition with AT1 blocker (ARB) significantly attenuated proteinuria and glomerulosclerosis in HIV-1 mice.
  
  
  CONCLUSIONS
  These results indicate that the protective effect of ARB is mediated through its receptors on cells other than podocytes, such as efferent arteriolar smooth muscle cells.
authors.affiliation: Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan. akihiro@jikei.ac.jp
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shimizu
authors.forename: Jianyong
authors.initials: J
authors.lastname: Zhong
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Hosoya
authors.forename: Iekuni
authors.initials: I
authors.lastname: Ichikawa
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015497:HIV-1; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050199:Podocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan