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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 late disease protocol.Representative light microscopy (10×) images of kidney cortex sections of uni-nephrectomized Fawn-Hooded Hypertensive rats double-stained with hematoxylin-eosin (H&E) and Jones silver stain. Tissue was harvested at week 30, i.e., after 12 weeks of treatment with: A: vehicle; B: Ang-(1-7) LD; C: Ang-(1-7) HD; D: Ang-(2-10) LD; E: Ang-(2-10) HD; F: captopril; G: losartan; H: glomerulosclerosis scores; I: tubular injury scores. Insets show a representative glomerulus. Significant segmental and global glomerulosclerosis, glomerular collapse and microcystic tubular dilatation is appreciated in all treatment groups, except in captopril-treated and losartan-treated rats. * = p<0.0001 compared to vehicle; ** = p<0.005 compared to vehicle; ¥ = p<0.05 compared to vehicle; n = 9/group except for vehicle group (n = 7) and Ang-(2-10) HD (n = 2). Data are in means ± SEM. LD = low-dose, HD = high-dose.
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pone-0110083-g007: Effect of Ang peptides on renal histology during the late disease protocol.Representative light microscopy (10×) images of kidney cortex sections of uni-nephrectomized Fawn-Hooded Hypertensive rats double-stained with hematoxylin-eosin (H&E) and Jones silver stain. Tissue was harvested at week 30, i.e., after 12 weeks of treatment with: A: vehicle; B: Ang-(1-7) LD; C: Ang-(1-7) HD; D: Ang-(2-10) LD; E: Ang-(2-10) HD; F: captopril; G: losartan; H: glomerulosclerosis scores; I: tubular injury scores. Insets show a representative glomerulus. Significant segmental and global glomerulosclerosis, glomerular collapse and microcystic tubular dilatation is appreciated in all treatment groups, except in captopril-treated and losartan-treated rats. * = p<0.0001 compared to vehicle; ** = p<0.005 compared to vehicle; ¥ = p<0.05 compared to vehicle; n = 9/group except for vehicle group (n = 7) and Ang-(2-10) HD (n = 2). Data are in means ± SEM. LD = low-dose, HD = high-dose.

Mentions: In the late disease model, all animals exhibited a substantial increase in systolic blood pressure 12 weeks after single nephrectomy (Fig. 3B). Thereafter, vehicle-treated rats continued to increase their blood pressure, raising it from 167±8 (at pump implantation) to 179±2 mmHg (after 6 weeks) (p<0.005) and maintaining it elevated at 185±3 mmHg after 12 weeks. Captopril and losartan decreased systolic blood pressure (156±7 and 155±5 mmHg at 6 weeks, and 145±5 and 146±5 mmHg after 12 weeks; for captopril and losartan, respectively; p<0.0001 vs. vehicle), suggesting that hypertension in FHH rats is partially Ang-II mediated. In contrast, low-dose Ang-(1-7) had no effect on blood pressure, low-dose Ang-(2-10) raised blood pressure after 12 weeks (194±3 mmHg; p<0.01 vs. vehicle), and both high-dose Ang-(1-7) and high-dose Ang-(2-10) raised blood pressure throughout the study (188±3 and 187±3 mmHg after 6 weeks, and 197±3 and 196±4 mmHg; for high-dose Ang-(1-7) and high-dose Ang-(2-10), respectively; p<0.001 vs. vehicle). However, only 2 high-dose Ang-(2-10)-treated rats survived until the end of the study. Ang-II-treated rats also exhibited increased blood pressure after 6 weeks, but no rats in this group survived beyond that time mark. Although the urine sodium excretion decreased in all groups after the 12-week therapy, no differences were found between groups (Table S1). Median proteinuria in vehicle-treated rats was 2 (1–5), 537 (184–862), 978 (433–2839) and 738 (622–2032) mg/day, at baseline (week 6), at the time of pump implantation (week 18), at week 24 and at week 30, respectively (Fig. 6). There was no change in 24-hour urinary protein excretion over the 12 weeks of treatment for any of the groups. However, the progression of the degree of proteinuria between weeks 18 and 24 was significantly attenuated by captopril (+342±289 vs. −225±453 mg/day, vehicle vs. captopril, respectively; p = 0.012). Proteinuria was not modified by either Ang-(1-7) or Ang-(2-10), regardless of dosing. Captopril significantly reduced the degree of glomerulosclerosis (0.88±0.2 vs. 2.29±0.9, p<0.0001) and tubular injury score (2.6±0.4 vs. 1.3±0.4, p<0.05) compared to vehicle, whereas losartan only reduced glomerulosclerosis (1.28±0.7 vs. 2.29±0.9, p<0.0005). None of the Ang-(1-7) and Ang-(2-10) treatments had an effect on structural damage (Fig. 7).


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 late disease protocol.Representative light microscopy (10×) images of kidney cortex sections of uni-nephrectomized Fawn-Hooded Hypertensive rats double-stained with hematoxylin-eosin (H&E) and Jones silver stain. Tissue was harvested at week 30, i.e., after 12 weeks of treatment with: A: vehicle; B: Ang-(1-7) LD; C: Ang-(1-7) HD; D: Ang-(2-10) LD; E: Ang-(2-10) HD; F: captopril; G: losartan; H: glomerulosclerosis scores; I: tubular injury scores. Insets show a representative glomerulus. Significant segmental and global glomerulosclerosis, glomerular collapse and microcystic tubular dilatation is appreciated in all treatment groups, except in captopril-treated and losartan-treated rats. * = p<0.0001 compared to vehicle; ** = p<0.005 compared to vehicle; ¥ = p<0.05 compared to vehicle; n = 9/group except for vehicle group (n = 7) and Ang-(2-10) HD (n = 2). Data are in means ± SEM. LD = low-dose, HD = high-dose.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110083-g007: Effect of Ang peptides on renal histology during the late disease protocol.Representative light microscopy (10×) images of kidney cortex sections of uni-nephrectomized Fawn-Hooded Hypertensive rats double-stained with hematoxylin-eosin (H&E) and Jones silver stain. Tissue was harvested at week 30, i.e., after 12 weeks of treatment with: A: vehicle; B: Ang-(1-7) LD; C: Ang-(1-7) HD; D: Ang-(2-10) LD; E: Ang-(2-10) HD; F: captopril; G: losartan; H: glomerulosclerosis scores; I: tubular injury scores. Insets show a representative glomerulus. Significant segmental and global glomerulosclerosis, glomerular collapse and microcystic tubular dilatation is appreciated in all treatment groups, except in captopril-treated and losartan-treated rats. * = p<0.0001 compared to vehicle; ** = p<0.005 compared to vehicle; ¥ = p<0.05 compared to vehicle; n = 9/group except for vehicle group (n = 7) and Ang-(2-10) HD (n = 2). Data are in means ± SEM. LD = low-dose, HD = high-dose.
Mentions: In the late disease model, all animals exhibited a substantial increase in systolic blood pressure 12 weeks after single nephrectomy (Fig. 3B). Thereafter, vehicle-treated rats continued to increase their blood pressure, raising it from 167±8 (at pump implantation) to 179±2 mmHg (after 6 weeks) (p<0.005) and maintaining it elevated at 185±3 mmHg after 12 weeks. Captopril and losartan decreased systolic blood pressure (156±7 and 155±5 mmHg at 6 weeks, and 145±5 and 146±5 mmHg after 12 weeks; for captopril and losartan, respectively; p<0.0001 vs. vehicle), suggesting that hypertension in FHH rats is partially Ang-II mediated. In contrast, low-dose Ang-(1-7) had no effect on blood pressure, low-dose Ang-(2-10) raised blood pressure after 12 weeks (194±3 mmHg; p<0.01 vs. vehicle), and both high-dose Ang-(1-7) and high-dose Ang-(2-10) raised blood pressure throughout the study (188±3 and 187±3 mmHg after 6 weeks, and 197±3 and 196±4 mmHg; for high-dose Ang-(1-7) and high-dose Ang-(2-10), respectively; p<0.001 vs. vehicle). However, only 2 high-dose Ang-(2-10)-treated rats survived until the end of the study. Ang-II-treated rats also exhibited increased blood pressure after 6 weeks, but no rats in this group survived beyond that time mark. Although the urine sodium excretion decreased in all groups after the 12-week therapy, no differences were found between groups (Table S1). Median proteinuria in vehicle-treated rats was 2 (1–5), 537 (184–862), 978 (433–2839) and 738 (622–2032) mg/day, at baseline (week 6), at the time of pump implantation (week 18), at week 24 and at week 30, respectively (Fig. 6). There was no change in 24-hour urinary protein excretion over the 12 weeks of treatment for any of the groups. However, the progression of the degree of proteinuria between weeks 18 and 24 was significantly attenuated by captopril (+342±289 vs. −225±453 mg/day, vehicle vs. captopril, respectively; p = 0.012). Proteinuria was not modified by either Ang-(1-7) or Ang-(2-10), regardless of dosing. Captopril significantly reduced the degree of glomerulosclerosis (0.88±0.2 vs. 2.29±0.9, p<0.0001) and tubular injury score (2.6±0.4 vs. 1.3±0.4, p<0.05) compared to vehicle, whereas losartan only reduced glomerulosclerosis (1.28±0.7 vs. 2.29±0.9, p<0.0005). None of the Ang-(1-7) and Ang-(2-10) treatments had an effect on structural damage (Fig. 7).

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