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

Velez JC, Janech MG, Hicks MP, Morinelli TA, Rodgers J, Self SE, Arthur JM, Fitzgibbon WR - PLoS ONE (2014)

Bottom Line: Unopposed angiotensin (Ang) II-mediated cellular effects may lead to progressive glomerulosclerosis.Exogenous administration of Ang-(1-7) and Ang-(2-10) did not lead to a significant increase in their corresponding intrarenal levels.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.

View Article: PubMed Central - PubMed

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.

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.

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Intrarenal Ang peptide content as measured by Parallel Reaction Monitoring.Kidneys were harvested at the end of the late disease protocol (after 12 weeks of therapy). Treatment arms are listed in the x-axes. ANOVA (p<0.05) indicates differences between groups that were detected, but no pairwise differences were significant; n = 5/group Data are in means ± SEM. L = low-dose, H = high-dose.
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pone-0110083-g008: Intrarenal Ang peptide content as measured by Parallel Reaction Monitoring.Kidneys were harvested at the end of the late disease protocol (after 12 weeks of therapy). Treatment arms are listed in the x-axes. ANOVA (p<0.05) indicates differences between groups that were detected, but no pairwise differences were significant; n = 5/group Data are in means ± SEM. L = low-dose, H = high-dose.

Mentions: The concentration of Ang peptides in kidney tissue was measured in kidneys harvested upon completion of the late disease model protocol, i.e., at 30 weeks of age, after 12 weeks of therapy. LC/MS/MS assay performance measures and peptide concentrations are summarized in Table 1 and Figure 8. Kidney Ang-I and Ang-(1-7) concentrations were different between groups, but evaluation by post-hoc comparison did not reveal any significant differences. Kidney levels of Ang-II and Ang-(2-10) were not different between groups. The statistical power of the test for both Ang-II and Ang-(2-10) were 0.27 and 0.05, respectively. When Ang-II levels were compared separately between vehicle and captopril groups using a Mann-Whitney U test, they were found to be lower in captopril-treated rats (p = 0.002) suggesting that the multi-group comparisons were underpowered. Because the majority of rats treated with high-dose Ang-(2-10) did not survive, we were unable to determine the effect of high-dose Ang-(2-10) treatment on Ang-(2-10) kidney content. Table S2 shows the range of previously reported intrarenal Ang peptide concentration in comparison to this study [17], [30]–[34].


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

Velez JC, Janech MG, Hicks MP, Morinelli TA, Rodgers J, Self SE, Arthur JM, Fitzgibbon WR - PLoS ONE (2014)

Intrarenal Ang peptide content as measured by Parallel Reaction Monitoring.Kidneys were harvested at the end of the late disease protocol (after 12 weeks of therapy). Treatment arms are listed in the x-axes. ANOVA (p<0.05) indicates differences between groups that were detected, but no pairwise differences were significant; n = 5/group Data are in means ± SEM. L = low-dose, H = high-dose.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206519&req=5

pone-0110083-g008: Intrarenal Ang peptide content as measured by Parallel Reaction Monitoring.Kidneys were harvested at the end of the late disease protocol (after 12 weeks of therapy). Treatment arms are listed in the x-axes. ANOVA (p<0.05) indicates differences between groups that were detected, but no pairwise differences were significant; n = 5/group Data are in means ± SEM. L = low-dose, H = high-dose.
Mentions: The concentration of Ang peptides in kidney tissue was measured in kidneys harvested upon completion of the late disease model protocol, i.e., at 30 weeks of age, after 12 weeks of therapy. LC/MS/MS assay performance measures and peptide concentrations are summarized in Table 1 and Figure 8. Kidney Ang-I and Ang-(1-7) concentrations were different between groups, but evaluation by post-hoc comparison did not reveal any significant differences. Kidney levels of Ang-II and Ang-(2-10) were not different between groups. The statistical power of the test for both Ang-II and Ang-(2-10) were 0.27 and 0.05, respectively. When Ang-II levels were compared separately between vehicle and captopril groups using a Mann-Whitney U test, they were found to be lower in captopril-treated rats (p = 0.002) suggesting that the multi-group comparisons were underpowered. Because the majority of rats treated with high-dose Ang-(2-10) did not survive, we were unable to determine the effect of high-dose Ang-(2-10) treatment on Ang-(2-10) kidney content. Table S2 shows the range of previously reported intrarenal Ang peptide concentration in comparison to this study [17], [30]–[34].

Bottom Line: Unopposed angiotensin (Ang) II-mediated cellular effects may lead to progressive glomerulosclerosis.Exogenous administration of Ang-(1-7) and Ang-(2-10) did not lead to a significant increase in their corresponding intrarenal levels.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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus