Angiotensin II Receptor Blocker Attenuates Intrarenal Renin-Angiotensin-System and Podocyte Injury in Rats with Myocardial Infarction

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.

Vitamin D modulates the association of circulating insulin-like growth factor-1 with carotid artery intima-media thickness

“…There was no significant interaction with total and LDL-cholesterol ( p = 0.71 and p = 0.80 in the BLSA sample, respectively; and p = 0.56 and p = 0.22 in the MAGIC one), glycated hemoglobin ( p = 0.14 in the BLSA sample, which included diabetic subjects), and hsCRP ( p = 0.65 in the MAGIC sample, in which CRP values were available). The IGF-1 system is also influenced by the RAAS [34,35]. Consistent with this, a significant interaction was found between IGF-1 and aldosterone in the MAGIC population ( p = 0.003).…”

Post‐partum podocyturia following pre‐eclamptic pregnancy

“…PE is a prominent risk factor for ESKD; 19 in women with three or more pregnancies, those with one PE pregnancy have a relative ESKD risk of 6.3 (95%CI: 4.1-9.9), while those with two PE pregnancies have a relative ESKD risk of 15.5 (95%CI: 7.8-30.8) compared with women with no PE pregnancies. 19 In an animal model, angiotensin receptor blocker (ARB) had a renoprotective effect via podocyte protection, 20 and was indeed shown to confer significant renal benefits in patients with type 2 diabetes and nephropathy, resulting in reduced proteinuria. 21 Although contraindicated in pregnancy, 22 use of ARB can be considered for renoprotection in post-partum women after PE pregnancy.…”

Comparison of renal impairment post-myocardial infarction with reduced and preserved left ventricular function in rats with normal renal function

“…Our previous study [3] and another report [4] have revealed the presence of injury to the podocytes, key parenchymal cells within the glomerular, in rat models with left ventricular dysfunction. Our prior research suggests that undue activation of the local renin angiotensin system (RAS) within the kidneys is an important marker for the pathogenesis of podocyte injury post-MI [3].…”

“…Experimental MI was induced in rats by left coronary artery ligation as described in our previous work [3,6,7]. Briefly, male Sprague-Dawley rats weighing about 300 g were anesthetized with sodium pentobarbital (intraperitoneal, 30 mg/kg), intubated, and then ventilated with a rodent respirator.…”

“…Our prior research suggests that undue activation of the local renin angiotensin system (RAS) within the kidneys is an important marker for the pathogenesis of podocyte injury post-MI [3]. The inhibition of RAS with angiotensin II type 1 receptor (AT-1R) blockers could prevent the initiation and deterioration of podocyte injury, providing new insight into the treatment of renal impairment post-MI with resultant left ventricular dysfunction [3,4].…”