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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 renal histology during the early disease protocol.Representative light microscopy (10×) images of kidney cortex specimens of uni-nephrectomized FHH rats double-stained with hematoxylin-eosin (H&E) and Jones silver stain. Tissue was harvested at the end of the early disease protocol, i.e., after 8 weeks of treatment with: A: vehicle; B: Ang II; C: Ang-(1-7) LD; D: Ang-(2-10) LD; and E: captopril. F: Glomerulosclerosis scores. G: Tubular injury scores. Insets show a representative glomerulus. Segmental glomerulosclerosis and microcystic tubular dilatation is appreciated in all treatment groups. * = p<0.01 compared to vehicle; ** = p<0.05 compared to vehicle n = 4/group, except captopril group (n = 5). Data are in means ± SEM. LD = low-dose.
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pone-0110083-g005: Effect of Ang peptides on renal histology during the early disease protocol.Representative light microscopy (10×) images of kidney cortex specimens of uni-nephrectomized FHH rats double-stained with hematoxylin-eosin (H&E) and Jones silver stain. Tissue was harvested at the end of the early disease protocol, i.e., after 8 weeks of treatment with: A: vehicle; B: Ang II; C: Ang-(1-7) LD; D: Ang-(2-10) LD; and E: captopril. F: Glomerulosclerosis scores. G: Tubular injury scores. Insets show a representative glomerulus. Segmental glomerulosclerosis and microcystic tubular dilatation is appreciated in all treatment groups. * = p<0.01 compared to vehicle; ** = p<0.05 compared to vehicle n = 4/group, except captopril group (n = 5). Data are in means ± SEM. LD = low-dose.

Mentions: In the early disease model, rats in all groups exhibited a small but consistent elevation in systolic blood pressure one week after single nephrectomy. Four weeks after initiation of therapy, systolic blood pressure in vehicle-treated rats increased (from 144±5, 161±4 mmHg, p = 0.01) and it remained elevated at 8 weeks (162±4 mmHg). A similar rise in arterial blood pressure was observed among animals treated with either low-dose Ang-(1-7) or low-dose Ang-(2-10). Ang-II induced a broader rise in mean systolic blood pressure compared to that in vehicle-treated rats after both 4 and 8 weeks of treatment. As expected, captopril decreased systolic blood pressure after 4 and 8 weeks of therapy (117±5 and 134±3, respectively); (p<0.0001 vs. vehicle) (Fig. 3A). Urine sodium excretion did not change over time in any of the groups, nor was a difference found between groups (Table S1). Urinary protein excretion increased between 4 and 8 weeks after the commencement of treatment (p<0.001). Median proteinuria in vehicle-treated rats was 89 (31–188) and 243 (91–402), mg/day, after 4 and 8 weeks, respectively (Fig. 4). Captopril significantly mitigated the development of proteinuria [14 (13–17) and 30 (25–33) mg/day, after 4 and 8 weeks of therapy, respectively; p = 0.014 vs. vehicle]. In contrast, proteinuria was not modified by either Ang-(1-7) or Ang-(2-10) at the doses tested and it was increased by Ang-II. Ang-II significantly worsened the degree of glomerulosclerosis (1.4±0.4 vs. 0.4±0.1; p<0.01) and tubular injury (1.6±0.2 vs. 0.8±0.2; p<0.05) compared to vehicle, whereas neither Ang-(1-7) nor Ang-(2-10) infusion changed the degree of structural damage. Captopril caused a significant reduction in glomerulosclerosis (0.1±0.1 vs. 0.4±0.1; p<0.05) but a non-significant reduction in tubular injury (Fig. 5).


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 renal histology during the early disease protocol.Representative light microscopy (10×) images of kidney cortex specimens of uni-nephrectomized FHH rats double-stained with hematoxylin-eosin (H&E) and Jones silver stain. Tissue was harvested at the end of the early disease protocol, i.e., after 8 weeks of treatment with: A: vehicle; B: Ang II; C: Ang-(1-7) LD; D: Ang-(2-10) LD; and E: captopril. F: Glomerulosclerosis scores. G: Tubular injury scores. Insets show a representative glomerulus. Segmental glomerulosclerosis and microcystic tubular dilatation is appreciated in all treatment groups. * = p<0.01 compared to vehicle; ** = p<0.05 compared to vehicle n = 4/group, except captopril group (n = 5). Data are in means ± SEM. LD = low-dose.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110083-g005: Effect of Ang peptides on renal histology during the early disease protocol.Representative light microscopy (10×) images of kidney cortex specimens of uni-nephrectomized FHH rats double-stained with hematoxylin-eosin (H&E) and Jones silver stain. Tissue was harvested at the end of the early disease protocol, i.e., after 8 weeks of treatment with: A: vehicle; B: Ang II; C: Ang-(1-7) LD; D: Ang-(2-10) LD; and E: captopril. F: Glomerulosclerosis scores. G: Tubular injury scores. Insets show a representative glomerulus. Segmental glomerulosclerosis and microcystic tubular dilatation is appreciated in all treatment groups. * = p<0.01 compared to vehicle; ** = p<0.05 compared to vehicle n = 4/group, except captopril group (n = 5). Data are in means ± SEM. LD = low-dose.
Mentions: In the early disease model, rats in all groups exhibited a small but consistent elevation in systolic blood pressure one week after single nephrectomy. Four weeks after initiation of therapy, systolic blood pressure in vehicle-treated rats increased (from 144±5, 161±4 mmHg, p = 0.01) and it remained elevated at 8 weeks (162±4 mmHg). A similar rise in arterial blood pressure was observed among animals treated with either low-dose Ang-(1-7) or low-dose Ang-(2-10). Ang-II induced a broader rise in mean systolic blood pressure compared to that in vehicle-treated rats after both 4 and 8 weeks of treatment. As expected, captopril decreased systolic blood pressure after 4 and 8 weeks of therapy (117±5 and 134±3, respectively); (p<0.0001 vs. vehicle) (Fig. 3A). Urine sodium excretion did not change over time in any of the groups, nor was a difference found between groups (Table S1). Urinary protein excretion increased between 4 and 8 weeks after the commencement of treatment (p<0.001). Median proteinuria in vehicle-treated rats was 89 (31–188) and 243 (91–402), mg/day, after 4 and 8 weeks, respectively (Fig. 4). Captopril significantly mitigated the development of proteinuria [14 (13–17) and 30 (25–33) mg/day, after 4 and 8 weeks of therapy, respectively; p = 0.014 vs. vehicle]. In contrast, proteinuria was not modified by either Ang-(1-7) or Ang-(2-10) at the doses tested and it was increased by Ang-II. Ang-II significantly worsened the degree of glomerulosclerosis (1.4±0.4 vs. 0.4±0.1; p<0.01) and tubular injury (1.6±0.2 vs. 0.8±0.2; p<0.05) compared to vehicle, whereas neither Ang-(1-7) nor Ang-(2-10) infusion changed the degree of structural damage. Captopril caused a significant reduction in glomerulosclerosis (0.1±0.1 vs. 0.4±0.1; p<0.05) but a non-significant reduction in tubular injury (Fig. 5).

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