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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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Experimental protocols.Schematic of treatment protocols employed to test the effect of early (Panel A) or late (Panel B) chronic intravenous administration of Ang-(1-7) and Ang-(2-10) on the progression of glomerulosclerosis in uni-nephrectomized FHH rats.
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pone-0110083-g001: Experimental protocols.Schematic of treatment protocols employed to test the effect of early (Panel A) or late (Panel B) chronic intravenous administration of Ang-(1-7) and Ang-(2-10) on the progression of glomerulosclerosis in uni-nephrectomized FHH rats.

Mentions: A schematic of the animal protocols is shown in Figure 1. In order to accelerate the development of glomerulosclerosis [25], rats (95–205 g) underwent left nephrectomy at 6 weeks of age. Following anesthesia, an incision was made in the left flank; the kidney was exposed and excised after ligation of the pedicle. One (early disease) or 12 (late disease) weeks following single nephrectomy, the rats underwent implantation of osmotic mini-pumps (Alzet models 2004 or 2006 Alza Corp., Palo Alto, CA) for intravenous delivery of either isotonic saline (vehicle) or Ang peptides. Under anesthesia, a mini-pump was placed in a subcutaneous pocket. A catheter (PE 50) attached to the pump was then tunneled subcutaneously around the neck and cannulated into the right jugular vein. Pumps were replaced once during the treatment period. For the early disease model, five groups of rats were examined. Either saline (n = 4) or 100 ng/kg/min (low-dose, LD) of Ang II (n = 4), Ang-(1-7) (n = 4) or Ang-(2-10) (n = 4) was infused for a total of 8 weeks. An additional group (n = 5) received captopril (100 mg/kg/d) in the drinking water throughout the treatment period. For the late disease model, eight groups of rats were examined. Saline (n = 7) or 100 ng/kg/min (low-dose, LD) or 400 ng/kg/min (high-dose, HD) of either Ang-(1-7) or Ang-(2-10), or Ang II (LD), was infused for a total of 12 weeks (n = 9 per Ang peptide treatment). The dosages of the Ang peptides were selected based on previous studies where Ang-(1-7) was similarly administered using implanted osmotic mini-pumps [13], [16], [17], [26]. Two further groups received captopril (100 mg/kg/d, n = 10) or losartan (20 mg/kg/d, n = 9) orally throughout the treatment period. Systemic blood pressure was measured by tail-cuff sphygmomanometer (Natume, Japan). Animals were placed on metabolic cages for urine collection at pre-specified time points. Urinary protein excretion was measured by the method of Lowry [27]. Urinary sodium concentration was measured by ion-selective electrodes. At sacrifice, kidneys were harvested for histological analysis and measurement of Ang peptide concentration.


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)

Experimental protocols.Schematic of treatment protocols employed to test the effect of early (Panel A) or late (Panel B) chronic intravenous administration of Ang-(1-7) and Ang-(2-10) on the progression of glomerulosclerosis in uni-nephrectomized FHH rats.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110083-g001: Experimental protocols.Schematic of treatment protocols employed to test the effect of early (Panel A) or late (Panel B) chronic intravenous administration of Ang-(1-7) and Ang-(2-10) on the progression of glomerulosclerosis in uni-nephrectomized FHH rats.
Mentions: A schematic of the animal protocols is shown in Figure 1. In order to accelerate the development of glomerulosclerosis [25], rats (95–205 g) underwent left nephrectomy at 6 weeks of age. Following anesthesia, an incision was made in the left flank; the kidney was exposed and excised after ligation of the pedicle. One (early disease) or 12 (late disease) weeks following single nephrectomy, the rats underwent implantation of osmotic mini-pumps (Alzet models 2004 or 2006 Alza Corp., Palo Alto, CA) for intravenous delivery of either isotonic saline (vehicle) or Ang peptides. Under anesthesia, a mini-pump was placed in a subcutaneous pocket. A catheter (PE 50) attached to the pump was then tunneled subcutaneously around the neck and cannulated into the right jugular vein. Pumps were replaced once during the treatment period. For the early disease model, five groups of rats were examined. Either saline (n = 4) or 100 ng/kg/min (low-dose, LD) of Ang II (n = 4), Ang-(1-7) (n = 4) or Ang-(2-10) (n = 4) was infused for a total of 8 weeks. An additional group (n = 5) received captopril (100 mg/kg/d) in the drinking water throughout the treatment period. For the late disease model, eight groups of rats were examined. Saline (n = 7) or 100 ng/kg/min (low-dose, LD) or 400 ng/kg/min (high-dose, HD) of either Ang-(1-7) or Ang-(2-10), or Ang II (LD), was infused for a total of 12 weeks (n = 9 per Ang peptide treatment). The dosages of the Ang peptides were selected based on previous studies where Ang-(1-7) was similarly administered using implanted osmotic mini-pumps [13], [16], [17], [26]. Two further groups received captopril (100 mg/kg/d, n = 10) or losartan (20 mg/kg/d, n = 9) orally throughout the treatment period. Systemic blood pressure was measured by tail-cuff sphygmomanometer (Natume, Japan). Animals were placed on metabolic cages for urine collection at pre-specified time points. Urinary protein excretion was measured by the method of Lowry [27]. Urinary sodium concentration was measured by ion-selective electrodes. At sacrifice, kidneys were harvested for histological analysis and measurement of Ang peptide concentration.

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