Abstract
The mechanisms and mediators underlying common renal impairment after myocardial infarction (MI) are still poorly understood. The present study aimed to test the hypothesis that angiotensin II type 1 receptor blockers (ARBs) provides renoprotective effects after MI by preventing augmented intrarenal renin-angiotensin-system (RAS)-induced podocyte injury. Sprague–Dawley rats that underwent ligation of their coronary arteries were treated with losartan (20 mg/kg/d) or vehicle for 3 or 9 weeks. Renal function, histology and molecular changes were assessed. The current study revealed that MI-induced glomerular podocyte injury was identified by increased immunostaining for desmin and p16ink4a, decreased immunostaining for Wilms’ tumor-1 and podocin mRNA expression, and an induced increase of blood cystatin C at both 3 and 9 weeks. These changes were associated with increased intrarenal angiotensin II levels and enhanced expressions of angiotensinogen mRNA and angiotensin II receptor mRNA and protein. These changes were also associated with decreased levels of insulin-like growth factor (IGF-1) and decreased expressions of IGF-1 receptor (IGF-1R) protein and mRNA and phosphorylated(p)-Akt protein at 9 weeks, as well as increased expressions of 8-hydroxy-2’-deoxyguanosine at both time points. Treatment with losartan significantly attenuated desmin- and p16ink4a-positive podocytes, restored podocin mRNA expression, and decreased blood cystatin C levels. Losartan also prevented RAS activation and oxidative stress and restored the IGF-1/IGF-1R/Akt pathway. In conclusion, ARBs prevent the progression of renal impairment after MI via podocyte protection, partially by inhibiting the activation of the local RAS with subsequent enhanced oxidative stress and an inhibited IGF-1/IGF-1R/Akt pathway.
Highlights
Myocardial infarction (MI) with resultant chronic heart failure (CHF) is a leading cause of mortality and morbidity in developed countries
Our previous study [6] revealed that MIinduced the local up-regulation of angiotensin II (AngII) type 1 receptor (AT1R) in the kidneys was associated with an increase in serum cystatin C levels which has been reported to be coincided with histopathologic intrarenal damage and augmented AngII in rats with acute kidney injury [7]
The present study indicates that podocyte injury and senescence are associated with a down-regulated insulin-like growth factor-1 (IGF-1)/ IGF-1 receptor (IGF-1R)/Akt pathway, while losartan could restore the activation of IGF-1/IGF-1R/Akt pathway and reduce podocyte injury
Summary
Myocardial infarction (MI) with resultant chronic heart failure (CHF) is a leading cause of mortality and morbidity in developed countries. It is of paramount importance to explore potential mechanisms involved in renal parenchymal damage in order to prevent the onset and progression of renal dysfunction after the initiation of MI with subsequent CHF. Our previous study [6] revealed that MIinduced the local up-regulation of AngII type 1 receptor (AT1R) in the kidneys was associated with an increase in serum cystatin C levels which has been reported to be coincided with histopathologic intrarenal damage and augmented AngII in rats with acute kidney injury [7]. The detrimental effects of enhanced intrarenal RAS on the pathogenesis of progressive renal impairment after heart failure may be attenuated by the intervention with RAS inhibitions [8,9,10,11]
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