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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 Next, I3C was withdrawn and rats were followed-up for another 12 weeks.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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Related in: MedlinePlus

Long-term effects of AT1-receptor blockade on hemodynamics.Mean arterial blood pressure (MAP) (A) and renal vascular resistance (RVR) (B) were significantly elevated in the I3C-treated group after renin-angiotensin system (RAS)- stimulation between 4–8 weeks of age. Losartan-treatment was able to prevent this completely. After stopping RAS-stimulation (after week 8) MAP and RVR decreased but remained significantly elevated, even until 20 weeks of age. Losartan treatment was also able to prevent the development of this sustained high blood pressure. The n for each group is presented in the bars of figure A. I3C, Indole-3-Carbinol; KW, kidney weight; MAP, mean arterial pressure.
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pone-0057815-g006: Long-term effects of AT1-receptor blockade on hemodynamics.Mean arterial blood pressure (MAP) (A) and renal vascular resistance (RVR) (B) were significantly elevated in the I3C-treated group after renin-angiotensin system (RAS)- stimulation between 4–8 weeks of age. Losartan-treatment was able to prevent this completely. After stopping RAS-stimulation (after week 8) MAP and RVR decreased but remained significantly elevated, even until 20 weeks of age. Losartan treatment was also able to prevent the development of this sustained high blood pressure. The n for each group is presented in the bars of figure A. I3C, Indole-3-Carbinol; KW, kidney weight; MAP, mean arterial pressure.

Mentions: After withdrawal of I3C from the diet, MAP decreased in the I3C-treated rats but remained highly elevated at 12 weeks of age. Even at 20 weeks of age, i.e. 12 weeks after stopping RAS-stimulation, MAP remained significantly higher when compared with the control rats. RVR demonstrated the same pattern. Four weeks of AT1R-blockade was able to completely prevent these effects. (Fig. 6A+B).


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)

Long-term effects of AT1-receptor blockade on hemodynamics.Mean arterial blood pressure (MAP) (A) and renal vascular resistance (RVR) (B) were significantly elevated in the I3C-treated group after renin-angiotensin system (RAS)- stimulation between 4–8 weeks of age. Losartan-treatment was able to prevent this completely. After stopping RAS-stimulation (after week 8) MAP and RVR decreased but remained significantly elevated, even until 20 weeks of age. Losartan treatment was also able to prevent the development of this sustained high blood pressure. The n for each group is presented in the bars of figure A. I3C, Indole-3-Carbinol; KW, kidney weight; MAP, mean arterial pressure.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057815-g006: Long-term effects of AT1-receptor blockade on hemodynamics.Mean arterial blood pressure (MAP) (A) and renal vascular resistance (RVR) (B) were significantly elevated in the I3C-treated group after renin-angiotensin system (RAS)- stimulation between 4–8 weeks of age. Losartan-treatment was able to prevent this completely. After stopping RAS-stimulation (after week 8) MAP and RVR decreased but remained significantly elevated, even until 20 weeks of age. Losartan treatment was also able to prevent the development of this sustained high blood pressure. The n for each group is presented in the bars of figure A. I3C, Indole-3-Carbinol; KW, kidney weight; MAP, mean arterial pressure.
Mentions: After withdrawal of I3C from the diet, MAP decreased in the I3C-treated rats but remained highly elevated at 12 weeks of age. Even at 20 weeks of age, i.e. 12 weeks after stopping RAS-stimulation, MAP remained significantly higher when compared with the control rats. RVR demonstrated the same pattern. Four weeks of AT1R-blockade was able to completely prevent these effects. (Fig. 6A+B).

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