Limits...
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 Next, I3C was withdrawn and rats were followed-up for another 12 weeks.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.

Show MeSH

Related in: MedlinePlus

Effects of anti-hypertensive treatments on gene expression of renal injury markers.Hydralazine treated rats expressed elevated levels of the renal injury markers KIM-1, OPN and NGAL. When compared with the untreated RAS-stimulated rats, gene expression levels demonstrated a decrease yet remained significantly elevated (A-C). This was in sharp contrast with losartan which caused a normalization of all parameters. PAI-1 expression was unaltered whereas nephrin was significantly decreased by hydralazine when compared with untreated RAS-stimulated rats (D+E). 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; PAI-1, plasminogen activator inhibitor-1.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585138&req=5

pone-0057815-g004: Effects of anti-hypertensive treatments on gene expression of renal injury markers.Hydralazine treated rats expressed elevated levels of the renal injury markers KIM-1, OPN and NGAL. When compared with the untreated RAS-stimulated rats, gene expression levels demonstrated a decrease yet remained significantly elevated (A-C). This was in sharp contrast with losartan which caused a normalization of all parameters. PAI-1 expression was unaltered whereas nephrin was significantly decreased by hydralazine when compared with untreated RAS-stimulated rats (D+E). 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; PAI-1, plasminogen activator inhibitor-1.

Mentions: RAS-stimulated rats developed albuminuria (Fig. 3A). Furthermore, the excretion of urinary KIM-1 and OPN was significantly increased (Fig. 3B+C) and followed a similar pattern as renal gene expression (Fig. 4). Losartan-treatment fully prevented the increase in expression of these renal injury markers and inhibited the excretion of them as well as of albumin. In contrast, in hydralazine treated-rats renal expression and urinary excretion of KIM-1, NGAL and albuminuria were in the same range as non-treated RAS-stimulated rats, whereas excretion of OPN was slightly decreased. These data are supported by analysis of PAS-D stained kidney slides and determination of renal pathology by means of GSI and TIS (Fig. 5). In short, whereas losartan completely prevents the development of an increased GSI and TIS, hydralazine is unable to improve renal pathology.


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)

Effects of anti-hypertensive treatments on gene expression of renal injury markers.Hydralazine treated rats expressed elevated levels of the renal injury markers KIM-1, OPN and NGAL. When compared with the untreated RAS-stimulated rats, gene expression levels demonstrated a decrease yet remained significantly elevated (A-C). This was in sharp contrast with losartan which caused a normalization of all parameters. PAI-1 expression was unaltered whereas nephrin was significantly decreased by hydralazine when compared with untreated RAS-stimulated rats (D+E). 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; PAI-1, plasminogen activator inhibitor-1.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057815-g004: Effects of anti-hypertensive treatments on gene expression of renal injury markers.Hydralazine treated rats expressed elevated levels of the renal injury markers KIM-1, OPN and NGAL. When compared with the untreated RAS-stimulated rats, gene expression levels demonstrated a decrease yet remained significantly elevated (A-C). This was in sharp contrast with losartan which caused a normalization of all parameters. PAI-1 expression was unaltered whereas nephrin was significantly decreased by hydralazine when compared with untreated RAS-stimulated rats (D+E). 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; PAI-1, plasminogen activator inhibitor-1.
Mentions: RAS-stimulated rats developed albuminuria (Fig. 3A). Furthermore, the excretion of urinary KIM-1 and OPN was significantly increased (Fig. 3B+C) and followed a similar pattern as renal gene expression (Fig. 4). Losartan-treatment fully prevented the increase in expression of these renal injury markers and inhibited the excretion of them as well as of albumin. In contrast, in hydralazine treated-rats renal expression and urinary excretion of KIM-1, NGAL and albuminuria were in the same range as non-treated RAS-stimulated rats, whereas excretion of OPN was slightly decreased. These data are supported by analysis of PAS-D stained kidney slides and determination of renal pathology by means of GSI and TIS (Fig. 5). In short, whereas losartan completely prevents the development of an increased GSI and TIS, hydralazine is unable to improve renal pathology.

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