title: Lack of renoprotective effect of chronic intravenous angiotensin-(1-7) or angiotensin-(2-10) in a rat model of focal segmental glomerulosclerosis.
abstract: Unopposed angiotensin (Ang) II-mediated cellular effects may lead to progressive glomerulosclerosis. While Ang-II can be locally generated in the kidneys, we previously showed that glomerular podocytes primarily convert Ang-I, the precursor of Ang-II, to Ang-(1-7) and Ang-(2-10), peptides that have been independently implicated in biological actions opposing those of Ang-II. Therefore, we hypothesized that Ang-(1-7) and Ang-(2-10) could be renoprotective in the fawn-hooded hypertensive rat, a model of focal segmental glomerulosclerosis. We evaluated the ability of 8-12 week-long intravenous administration of either Ang-(1-7) or Ang-(2-10) (100-400 ng/kg/min) to reduce glomerular injury in uni-nephrectomized fawn-hooded hypertensive rats, early or late in the disease. Vehicle-treated rats developed hypertension and lesions of focal segmental glomerulosclerosis. No reduction in glomerular damage was observed, as measured by either 24-hour urinary protein excretion or histological examination of glomerulosclerosis, upon Ang-(1-7) or Ang-(2-10) administration, regardless of peptide dose or disease stage. On the contrary, when given at 400 ng/kg/min, both peptides induced a further increase in systolic blood pressure. Content of Ang peptides was measured by parallel reaction monitoring in kidneys harvested at sacrifice. Exogenous administration of Ang-(1-7) and Ang-(2-10) did not lead to a significant increase in their corresponding intrarenal levels. However, the relative abundance of Ang-(1-7) with respect to Ang-II was increased in kidney homogenates of Ang-(1-7)-treated rats. We conclude that chronic intravenous administration of Ang-(1-7) or Ang-(2-10) does not ameliorate glomerular damage in a rat model of focal segmental glomerulosclerosis and may induce a further rise in blood pressure, potentially aggravating glomerular injury.
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America; Medical Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States of America.
authors.forename: Juan Carlos Q
authors.initials: JC
authors.lastname: Velez
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Janech
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Megan P
authors.initials: MP
authors.lastname: Hicks
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Morinelli
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Jessalyn
authors.initials: J
authors.lastname: Rodgers
authors.affiliation: Department of Pathology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Self
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America; Medical Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Arthur
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Fitzgibbon
mesh_terms: D000803:Angiotensin I / Q000008:administration & dosage*; D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D004334:Drug Administration Schedule; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007275:Injections, Intravenous; D008297:Male; D009392:Nephrectomy; D010446:Peptide Fragments / Q000008:administration & dosage*; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011869:Radioligand Assay; D051381:Rats; D017211:Treatment Failure
chemical_list: D010446:Peptide Fragments; D000804:Angiotensin II; D000803:Angiotensin I; C118790:angiotensin I (1-7)