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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 Next, I3C was withdrawn and rats were followed-up for another 12 weeks.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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Long-term effects of of AT1-receptor blockade on gene expression of renal injury markers.Gene expression of the renal injury markers NGAL, KIM-1 and OPN was highly elevated after 4 weeks of RAS-stimulation (A–C). Stopping RAS-stimulation led to a decrease in expression, nevertheless, the levels remained significantly elevated even until 20 weeks of age. At first, PAI-1 expression remained at control levels and was increased at 12 and 20 weeks of age in the RAS-stimulated rats (D). Finally, the expression of nephrin demonstrated little to no differences (E). Only a small decrease in expression was observed at 12 weeks of age in the RAS-stimulated rats. Losartan-treatment was able to prevent all of the effects on the renal injury markers. In adult rats which do not develop sustained hypertension after 4 weeks of RAS-stimulation a normalization of all renal injury markers occurs within 4 weeks after stopping the stimulation (data not shown). The n for each group is presented in the bars of figure A. I3C, Indole-3-Carbinol; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase associated lipocalin; OPN, osteopontin; PAI-1, plasminogen activator inhibitor-1.
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pone-0057815-g007: Long-term effects of of AT1-receptor blockade on gene expression of renal injury markers.Gene expression of the renal injury markers NGAL, KIM-1 and OPN was highly elevated after 4 weeks of RAS-stimulation (A–C). Stopping RAS-stimulation led to a decrease in expression, nevertheless, the levels remained significantly elevated even until 20 weeks of age. At first, PAI-1 expression remained at control levels and was increased at 12 and 20 weeks of age in the RAS-stimulated rats (D). Finally, the expression of nephrin demonstrated little to no differences (E). Only a small decrease in expression was observed at 12 weeks of age in the RAS-stimulated rats. Losartan-treatment was able to prevent all of the effects on the renal injury markers. In adult rats which do not develop sustained hypertension after 4 weeks of RAS-stimulation a normalization of all renal injury markers occurs within 4 weeks after stopping the stimulation (data not shown). The n for each group is presented in the bars of figure A. I3C, Indole-3-Carbinol; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase associated lipocalin; OPN, osteopontin; PAI-1, plasminogen activator inhibitor-1.

Mentions: Stopping RAS-stimulation led to a decrease in expression of the renal injury markers KIM-1, OPN and NGAL. Nevertheless, the levels remained significantly elevated even until 20 weeks of age (Fig. 7A–C). Whereas the increase of these markers was present immediately at 8 weeks of age, PAI-1 expression remained at control levels at first. Later on, PAI-1 demonstrated increased expression levels in the RAS-stimulated rats at 12 and 20 weeks of age (Fig. 7D). Finally, the expression of nephrin demonstrated little to no differences (Fig. 7E). Only a small decrease in expression was observed at 12 weeks of age in the RAS-stimulated rats. Further evaluation of the glomerular filtration barrier was done by immunohistochemical analysis of WT-1 expression at 8 weeks of age, i.e. when albuminuria was most prominent. Again no differences were observed (Fig. 8).


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 of AT1-receptor blockade on gene expression of renal injury markers.Gene expression of the renal injury markers NGAL, KIM-1 and OPN was highly elevated after 4 weeks of RAS-stimulation (A–C). Stopping RAS-stimulation led to a decrease in expression, nevertheless, the levels remained significantly elevated even until 20 weeks of age. At first, PAI-1 expression remained at control levels and was increased at 12 and 20 weeks of age in the RAS-stimulated rats (D). Finally, the expression of nephrin demonstrated little to no differences (E). Only a small decrease in expression was observed at 12 weeks of age in the RAS-stimulated rats. Losartan-treatment was able to prevent all of the effects on the renal injury markers. In adult rats which do not develop sustained hypertension after 4 weeks of RAS-stimulation a normalization of all renal injury markers occurs within 4 weeks after stopping the stimulation (data not shown). The n for each group is presented in the bars of figure A. I3C, Indole-3-Carbinol; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase associated lipocalin; OPN, osteopontin; PAI-1, plasminogen activator inhibitor-1.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057815-g007: Long-term effects of of AT1-receptor blockade on gene expression of renal injury markers.Gene expression of the renal injury markers NGAL, KIM-1 and OPN was highly elevated after 4 weeks of RAS-stimulation (A–C). Stopping RAS-stimulation led to a decrease in expression, nevertheless, the levels remained significantly elevated even until 20 weeks of age. At first, PAI-1 expression remained at control levels and was increased at 12 and 20 weeks of age in the RAS-stimulated rats (D). Finally, the expression of nephrin demonstrated little to no differences (E). Only a small decrease in expression was observed at 12 weeks of age in the RAS-stimulated rats. Losartan-treatment was able to prevent all of the effects on the renal injury markers. In adult rats which do not develop sustained hypertension after 4 weeks of RAS-stimulation a normalization of all renal injury markers occurs within 4 weeks after stopping the stimulation (data not shown). The n for each group is presented in the bars of figure A. I3C, Indole-3-Carbinol; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase associated lipocalin; OPN, osteopontin; PAI-1, plasminogen activator inhibitor-1.
Mentions: Stopping RAS-stimulation led to a decrease in expression of the renal injury markers KIM-1, OPN and NGAL. Nevertheless, the levels remained significantly elevated even until 20 weeks of age (Fig. 7A–C). Whereas the increase of these markers was present immediately at 8 weeks of age, PAI-1 expression remained at control levels at first. Later on, PAI-1 demonstrated increased expression levels in the RAS-stimulated rats at 12 and 20 weeks of age (Fig. 7D). Finally, the expression of nephrin demonstrated little to no differences (Fig. 7E). Only a small decrease in expression was observed at 12 weeks of age in the RAS-stimulated rats. Further evaluation of the glomerular filtration barrier was done by immunohistochemical analysis of WT-1 expression at 8 weeks of age, i.e. when albuminuria was most prominent. Again no differences were observed (Fig. 8).

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