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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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Effect of Ang peptides on blood pressure.Tail-cuff systolic blood pressure readings in uni-nephrectomized FHH rats obtained in A: early disease protocol [n = 4/group, except captopril group (n = 5)]: at the time of uni-nephrectomy (week 6), initial mini-pump implantation (week 7), mini-pump exchange (week 11), and sacrifice (week 15); or B: late disease protocol [n = 9/group, except vehicle group (n = 7)]: at the time of uni-nephrectomy (week 6), initial mini-pump implantation (week 18), mini-pump exchange (week 24), and sacrifice (week 30). * = significantly lower than vehicle (p = 0.014); ¥ = significantly higher than vehicle (p<0.001). Only 2 rats from the Ang-(2-10) HD group and none of the Ang-II group were alive at week 30. Data are in means ± SEM. SBP = systolic blood pressure, LD = low-dose, HD = high-dose.
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pone-0110083-g003: Effect of Ang peptides on blood pressure.Tail-cuff systolic blood pressure readings in uni-nephrectomized FHH rats obtained in A: early disease protocol [n = 4/group, except captopril group (n = 5)]: at the time of uni-nephrectomy (week 6), initial mini-pump implantation (week 7), mini-pump exchange (week 11), and sacrifice (week 15); or B: late disease protocol [n = 9/group, except vehicle group (n = 7)]: at the time of uni-nephrectomy (week 6), initial mini-pump implantation (week 18), mini-pump exchange (week 24), and sacrifice (week 30). * = significantly lower than vehicle (p = 0.014); ¥ = significantly higher than vehicle (p<0.001). Only 2 rats from the Ang-(2-10) HD group and none of the Ang-II group were alive at week 30. Data are in means ± SEM. SBP = systolic blood pressure, LD = low-dose, HD = high-dose.

Mentions: In accordance to previous studies utilizing the uni-nephrectomized FHH rat model [25], [29], all animals exhibited a progressive increase over time in systemic blood pressure, urinary protein excretion and parenchymal injury characterized by focal segmental glomerulosclerosis and microcystic tubular dilatation. In the late disease model, approximately 80% of the glomeruli were affected with some degree of glomerulosclerosis, either segmental or global, demonstrating the robustness of the animal model. The changes observed in systolic blood pressure during the early and late disease models are shown in Figure 3. Data on changes in body weight, kidney weight and urine volume are presented in Table 2.


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)

Effect of Ang peptides on blood pressure.Tail-cuff systolic blood pressure readings in uni-nephrectomized FHH rats obtained in A: early disease protocol [n = 4/group, except captopril group (n = 5)]: at the time of uni-nephrectomy (week 6), initial mini-pump implantation (week 7), mini-pump exchange (week 11), and sacrifice (week 15); or B: late disease protocol [n = 9/group, except vehicle group (n = 7)]: at the time of uni-nephrectomy (week 6), initial mini-pump implantation (week 18), mini-pump exchange (week 24), and sacrifice (week 30). * = significantly lower than vehicle (p = 0.014); ¥ = significantly higher than vehicle (p<0.001). Only 2 rats from the Ang-(2-10) HD group and none of the Ang-II group were alive at week 30. Data are in means ± SEM. SBP = systolic blood pressure, LD = low-dose, HD = high-dose.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110083-g003: Effect of Ang peptides on blood pressure.Tail-cuff systolic blood pressure readings in uni-nephrectomized FHH rats obtained in A: early disease protocol [n = 4/group, except captopril group (n = 5)]: at the time of uni-nephrectomy (week 6), initial mini-pump implantation (week 7), mini-pump exchange (week 11), and sacrifice (week 15); or B: late disease protocol [n = 9/group, except vehicle group (n = 7)]: at the time of uni-nephrectomy (week 6), initial mini-pump implantation (week 18), mini-pump exchange (week 24), and sacrifice (week 30). * = significantly lower than vehicle (p = 0.014); ¥ = significantly higher than vehicle (p<0.001). Only 2 rats from the Ang-(2-10) HD group and none of the Ang-II group were alive at week 30. Data are in means ± SEM. SBP = systolic blood pressure, LD = low-dose, HD = high-dose.
Mentions: In accordance to previous studies utilizing the uni-nephrectomized FHH rat model [25], [29], all animals exhibited a progressive increase over time in systemic blood pressure, urinary protein excretion and parenchymal injury characterized by focal segmental glomerulosclerosis and microcystic tubular dilatation. In the late disease model, approximately 80% of the glomeruli were affected with some degree of glomerulosclerosis, either segmental or global, demonstrating the robustness of the animal model. The changes observed in systolic blood pressure during the early and late disease models are shown in Figure 3. Data on changes in body weight, kidney weight and urine volume are presented in Table 2.

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