Lack of renoprotective effect of chronic intravenous angiotensin-(1-7) or angiotensin-(2-10) in a rat model of focal segmental glomerulosclerosis

• Published in: PloS one 2014-10, Vol.9 (10), p.e110083-e110083
• Main Authors: Velez, Juan Carlos Q, Janech, Michael G, Hicks, Megan P, Morinelli, Thomas A, Rodgers, Jessalyn, Self, Sally E, Arthur, John M, Fitzgibbon, Wayne R
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin I - administration & dosage; Angiotensin II - administration & dosage; Animals; Biology and Life Sciences; Blood; Blood pressure; Diabetes; Disease; Drug Administration Schedule; Enzymes; Excretion; Glomerulosclerosis, Focal Segmental - complications; Glomerulosclerosis, Focal Segmental - drug therapy; Glomerulosclerosis, Focal Segmental - metabolism; Glomerulosclerosis, Focal Segmental - pathology; HEK293 Cells; Humans; Hypertension; Hypertension - complications; Hypertension - drug therapy; Hypertension - metabolism; Hypertension - pathology; Injections, Intravenous; Injury prevention; Intravenous administration; Kidneys; Laboratory animals; Lesions; Male; Medicine; Medicine and Health Sciences; Nephrectomy; Nephrology; Peptide Fragments - administration & dosage; Peptides; Physical Sciences; Physiology; Podocytes - drug effects; Podocytes - metabolism; Podocytes - pathology; Radioligand Assay; Rats; Relative abundance; Rodents; Treatment Failure
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0110083

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.