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 Next, I3C was withdrawn and rats were followed-up for another 12 weeks.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

Long-term effects of AT1-receptor blockade on renal injury.Four weeks of RAS-stimulation induced irreversible renal damage. Despite high levels of circulating RAS-components, supplementary AT1R-blockade was able to completely prevent the development of renal pathology over time. The n for each group is presented in the bars of the GSI. GSI, glomerulosclerosis index; I3C, Indole-3-Carbinol; TIS, tubulointerstitial score.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585138&req=5

pone-0057815-g010: Long-term effects of AT1-receptor blockade on renal injury.Four weeks of RAS-stimulation induced irreversible renal damage. Despite high levels of circulating RAS-components, supplementary AT1R-blockade was able to completely prevent the development of renal pathology over time. The n for each group is presented in the bars of the GSI. GSI, glomerulosclerosis index; I3C, Indole-3-Carbinol; TIS, tubulointerstitial score.

Mentions: In figure 9 the urinary excretion levels of KIM-1 and OPN are presented and demonstrate similar patterns as observed for renal gene expression. In addition, albuminuria remained significantly present even 12 weeks after stopping RAS-stimulation (Fig. 9A). Losartan fully blocked all these effects, which is again supported by the absence of renal pathology when compared with untreated age-matched RAS-stimulated rats (Fig. 10).


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 renal injury.Four weeks of RAS-stimulation induced irreversible renal damage. Despite high levels of circulating RAS-components, supplementary AT1R-blockade was able to completely prevent the development of renal pathology over time. The n for each group is presented in the bars of the GSI. GSI, glomerulosclerosis index; I3C, Indole-3-Carbinol; TIS, tubulointerstitial score.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057815-g010: Long-term effects of AT1-receptor blockade on renal injury.Four weeks of RAS-stimulation induced irreversible renal damage. Despite high levels of circulating RAS-components, supplementary AT1R-blockade was able to completely prevent the development of renal pathology over time. The n for each group is presented in the bars of the GSI. GSI, glomerulosclerosis index; I3C, Indole-3-Carbinol; TIS, tubulointerstitial score.
Mentions: In figure 9 the urinary excretion levels of KIM-1 and OPN are presented and demonstrate similar patterns as observed for renal gene expression. In addition, albuminuria remained significantly present even 12 weeks after stopping RAS-stimulation (Fig. 9A). Losartan fully blocked all these effects, which is again supported by the absence of renal pathology when compared with untreated age-matched RAS-stimulated rats (Fig. 10).

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