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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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Ratios of intrarenal Ang peptide abundance.Kidneys were harvested at the end of the late disease protocol (after 12 weeks of therapy). Treatment arms are listed in the x-axes. Group specific post-hoc pairwise differences (P<0.05) are indicated by letters. Equivalent letters indicate groups that are not significantly different from each other and different letters indicate a significant difference was detected between groups. ANOVA (p<0.05) indicates if differences between groups 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-g009: Ratios of intrarenal Ang peptide abundance.Kidneys were harvested at the end of the late disease protocol (after 12 weeks of therapy). Treatment arms are listed in the x-axes. Group specific post-hoc pairwise differences (P<0.05) are indicated by letters. Equivalent letters indicate groups that are not significantly different from each other and different letters indicate a significant difference was detected between groups. ANOVA (p<0.05) indicates if differences between groups were detected, but no pairwise differences were significant; n = 5/group Data are in means ± SEM. L = low-dose, H = high-dose.

Mentions: Although individual Ang-(1-7) peptide levels were not elevated in the Ang-(1-7) infused groups, the ratio of Ang-(1-7)/Ang-II content was higher in both the low dose and high dose groups compared to vehicle (Figure 9), suggesting an effect of Ang-(1-7) infusion on Ang peptide balance in the kidney, but were not different from captopril treatment, a finding that is in line with a known effect of ACE inhibition on Ang-(1-7) degradation and Ang-II generation [32]. Low-dose Ang-(1-7) infusion also resulted in an elevation in the Ang-I/Ang-II and Ang-(2-10)/Ang-II ratios compared to vehicle-infused controls (p = 0.01) but was not different from captopril-treated animals. The effects of Ang-(1-7) and captopril on Ang-(1-7)/Ang-I and Ang-(2-10)/Ang-I ratios could not be discerned by post hoc comparison, despite the fact that significant differences between groups were detected (ANOVA, p<0.05). Infusion of low-dose Ang-(2-10) did not significantly change any ratio compared to vehicle.


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)

Ratios of intrarenal Ang peptide abundance.Kidneys were harvested at the end of the late disease protocol (after 12 weeks of therapy). Treatment arms are listed in the x-axes. Group specific post-hoc pairwise differences (P<0.05) are indicated by letters. Equivalent letters indicate groups that are not significantly different from each other and different letters indicate a significant difference was detected between groups. ANOVA (p<0.05) indicates if differences between groups 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-g009: Ratios of intrarenal Ang peptide abundance.Kidneys were harvested at the end of the late disease protocol (after 12 weeks of therapy). Treatment arms are listed in the x-axes. Group specific post-hoc pairwise differences (P<0.05) are indicated by letters. Equivalent letters indicate groups that are not significantly different from each other and different letters indicate a significant difference was detected between groups. ANOVA (p<0.05) indicates if differences between groups were detected, but no pairwise differences were significant; n = 5/group Data are in means ± SEM. L = low-dose, H = high-dose.
Mentions: Although individual Ang-(1-7) peptide levels were not elevated in the Ang-(1-7) infused groups, the ratio of Ang-(1-7)/Ang-II content was higher in both the low dose and high dose groups compared to vehicle (Figure 9), suggesting an effect of Ang-(1-7) infusion on Ang peptide balance in the kidney, but were not different from captopril treatment, a finding that is in line with a known effect of ACE inhibition on Ang-(1-7) degradation and Ang-II generation [32]. Low-dose Ang-(1-7) infusion also resulted in an elevation in the Ang-I/Ang-II and Ang-(2-10)/Ang-II ratios compared to vehicle-infused controls (p = 0.01) but was not different from captopril-treated animals. The effects of Ang-(1-7) and captopril on Ang-(1-7)/Ang-I and Ang-(2-10)/Ang-I ratios could not be discerned by post hoc comparison, despite the fact that significant differences between groups were detected (ANOVA, p<0.05). Infusion of low-dose Ang-(2-10) did not significantly change any ratio compared to vehicle.

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