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Irreversible renal damage after transient renin-angiotensin system stimulation: involvement of an AT1-receptor mediated immune response.

Heijnen BF, Nelissen J, van Essen H, Fazzi GE, Cohen Tervaert JW, Peutz-Kootstra CJ, Mullins JJ, Schalkwijk CG, Janssen BJ, Struijker-Boudier HA - PLoS ONE (2013)

Bottom Line: Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4-8 weeks.At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis.Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. bart.heijnen@maastrichtuniversity.nl

ABSTRACT
Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-Ren2 transgenic rats. In our current study we hypothesized that activation of the AT1-receptor (AT1R) leads to a T-cell response causing irreversible impairment of renal function and hypertension. Cyp1a1-Ren2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C). Rats were fed a I3C diet between 4-8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4-8 weeks. Rats were placed for 24h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. The development of sustained hypertension was completely prevented by losartan, whereas hydralazine only caused a partial decrease in BP. Markers of renal damage: KIM-1 and osteopontin were highly expressed in urine and kidney samples of I3C-treated rats, even until 20 weeks of age. Additionally, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas the expression of T-helper 1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes. In young Cyp1a1-Ren2 rats AT1R activation leads to induction of an immune response, causing a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension.

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Experimental setup.Cyp1a1-Ren2 rats were treated from 4–8 weeks of age. The I3C-treated rats received 0.3% I3C via the diet, whereas control rats received standard rat chow. Losartan was administered via s.c. implanted minipumps at a dose of 20 mg kg−1 day−1. Losartan and I3C-treatment were stopped at 8 weeks of age and rats were followed-up until 20 weeks of age, i.e. 12 weeks after stopping the treatment-regiments. Ctrl, Control; I3C, Indole-3-Carbinol.
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pone-0057815-g001: Experimental setup.Cyp1a1-Ren2 rats were treated from 4–8 weeks of age. The I3C-treated rats received 0.3% I3C via the diet, whereas control rats received standard rat chow. Losartan was administered via s.c. implanted minipumps at a dose of 20 mg kg−1 day−1. Losartan and I3C-treatment were stopped at 8 weeks of age and rats were followed-up until 20 weeks of age, i.e. 12 weeks after stopping the treatment-regiments. Ctrl, Control; I3C, Indole-3-Carbinol.

Mentions: In a second set of experiments we further evaluated the underlying immune response and tested whether the 4 weeks of AT1R-blockade, during the 4 weeks I3C-treatment with high circulating (pro-)renin and Ang II levels, was able to completely prevent the development of hypertension and renal damage over time. For this purpose we included 4 groups: control, control+losartan, I3C-treated and I3C-treated+losartan, and followed them up until 20 weeks of age. At 8 weeks of age the osmotic minipumps were carefully removed under isoflurane anesthesia and buprenorphine analgesia. At 8, 12 and 20 weeks of age animals were placed in metabolic cages, direct arterial blood pressure and RVR were determined and the rats were sacrificed and the organs were processed for further analysis. Figure 1 illustrates the experimental setup of this in vivo experiment.


Irreversible renal damage after transient renin-angiotensin system stimulation: involvement of an AT1-receptor mediated immune response.

Heijnen BF, Nelissen J, van Essen H, Fazzi GE, Cohen Tervaert JW, Peutz-Kootstra CJ, Mullins JJ, Schalkwijk CG, Janssen BJ, Struijker-Boudier HA - PLoS ONE (2013)

Experimental setup.Cyp1a1-Ren2 rats were treated from 4–8 weeks of age. The I3C-treated rats received 0.3% I3C via the diet, whereas control rats received standard rat chow. Losartan was administered via s.c. implanted minipumps at a dose of 20 mg kg−1 day−1. Losartan and I3C-treatment were stopped at 8 weeks of age and rats were followed-up until 20 weeks of age, i.e. 12 weeks after stopping the treatment-regiments. Ctrl, Control; I3C, Indole-3-Carbinol.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585138&req=5

pone-0057815-g001: Experimental setup.Cyp1a1-Ren2 rats were treated from 4–8 weeks of age. The I3C-treated rats received 0.3% I3C via the diet, whereas control rats received standard rat chow. Losartan was administered via s.c. implanted minipumps at a dose of 20 mg kg−1 day−1. Losartan and I3C-treatment were stopped at 8 weeks of age and rats were followed-up until 20 weeks of age, i.e. 12 weeks after stopping the treatment-regiments. Ctrl, Control; I3C, Indole-3-Carbinol.
Mentions: In a second set of experiments we further evaluated the underlying immune response and tested whether the 4 weeks of AT1R-blockade, during the 4 weeks I3C-treatment with high circulating (pro-)renin and Ang II levels, was able to completely prevent the development of hypertension and renal damage over time. For this purpose we included 4 groups: control, control+losartan, I3C-treated and I3C-treated+losartan, and followed them up until 20 weeks of age. At 8 weeks of age the osmotic minipumps were carefully removed under isoflurane anesthesia and buprenorphine analgesia. At 8, 12 and 20 weeks of age animals were placed in metabolic cages, direct arterial blood pressure and RVR were determined and the rats were sacrificed and the organs were processed for further analysis. Figure 1 illustrates the experimental setup of this in vivo experiment.

Bottom Line: Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4-8 weeks.At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis.Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. bart.heijnen@maastrichtuniversity.nl

ABSTRACT
Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-Ren2 transgenic rats. In our current study we hypothesized that activation of the AT1-receptor (AT1R) leads to a T-cell response causing irreversible impairment of renal function and hypertension. Cyp1a1-Ren2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C). Rats were fed a I3C diet between 4-8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4-8 weeks. Rats were placed for 24h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. The development of sustained hypertension was completely prevented by losartan, whereas hydralazine only caused a partial decrease in BP. Markers of renal damage: KIM-1 and osteopontin were highly expressed in urine and kidney samples of I3C-treated rats, even until 20 weeks of age. Additionally, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas the expression of T-helper 1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes. In young Cyp1a1-Ren2 rats AT1R activation leads to induction of an immune response, causing a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension.

Show MeSH
Related in: MedlinePlus