Possible contribution of the non‐proteolytic activation of prorenin to the development of insulin resistance in fructose‐fed rats

Abstract

Recent studies have shown that blocking non-proteolytically activated prorenin with a decoy peptide for the handle region of the prorenin prosegment (HRP) inhibits the development of microvascular complications in diabetic animals. In the present study, we investigated whether non-proteolytic activation of prorenin contributes to the development of fructose-induced insulin resistance. Rats were fed a standard diet (n = 10), a 60% high fructose diet (n = 16), or a high fructose diet + HRP (0.1 mg kg −1 day −1 , n = 16) for 10 weeks. Fructose-fed rats showed higher systolic blood pressure (SBP), fasting plasma triglycerides, total cholesterol and insulin levels; which, except for SBP, were suppressed by HRP. The responses of plasma glucose and insulin levels to oral glucose loading were significantly greater in fructose-fed rats than in standard diet-fed rats. The HRP normalized the enhanced responses of plasma glucose and insulin levels that were observed in fructose-fed rats. Moreover, HRP suppressed the enhanced prorenin activation and angiotensin II formation in the soleus muscle of fructose-fed rats. These data suggest that local angiotensin II generation in skeletal muscle, induced by non-proteolytic activation of prorenin, contributes to the development of insulin resistance induced by a high fructose diet.

(Pro)renin and its receptors: pathophysiological implications

“…However, in apparent contrast with the above in vitro results on glucose-induced (P)RR upregulation in mesangial cells, HRP (0.2 mg/kg of body weight per day) did not suppress the elevated renal interstitial AngII in diabetic rats, nor normalized the increased (P)RR expression in this model [88]. In fact, the lack of effect of HRP on (P)RR expression appears to be a general phenomenon in in vivo studies applying this drug [76,78,[89][90][91]. AT 1 receptor blockade with valsartan did normalize (P)RR expression, and both HRP and valsartan suppressed the up-regulated TGFβ1 levels in the diabetic rat kidney [92].…”

“…Moreover, in diabetic SHRsp [stroke-prone SHR (spontaneously hypertensive rats)] on a high-salt diet, the beneficial effects of HRP (0.1 mg/kg of body weight per day) and ACE inhibition on protein excretion and heart weight (but not on renal and cardiac AngII content) were additive [77]. HRP (0.1 mg/kg of body weight per day) also normalized the elevated fasting plasma triacyglycerols (triglycerides), total cholesterol and insulin levels in rats fed high fructose, without affecting the elevated BP in these animals [78]. Taken together, these findings suggest that HRP exerts beneficial effects in a variety of (diabetic) models in an AngIIindependent manner.…”

(Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice

“…MI mice were randomly grouped to be treated with saline or HRP (0.1 mg·kg body wt Ϫ1 ·day Ϫ1 ; GeneDesign, Osaka, Japan) subcutaneously for 4 wk using an osmotic minipump (model 2004 ALZET, CA). The concentration of HRP and the duration of treatment in the present study were chosen based on the previous study of their efficacy (33). Experiments were performed after 4 wk of operation in the following four groups: 1) Sham (n ϭ 10), 2) ShamϩHRP (n ϭ 10), 3) MI (n ϭ 10), and 4) MIϩHRP (n ϭ 10).…”

“…Therefore, these clinical studies suggest that mild insulin resistance can contribute to the exacerbation of HF. A previous study demonstrated that HRP ameliorated glucose intolerance in fructose-fed rats (33). Furthermore, the effect of HRP on insulin resistance was due to normalization of insulin signaling, including serine phosphorylation of Akt and GLUT4 translocation in the skeletal muscle from MI.…”

“…The nonproteolytically activated prorenin can generate angiotensin I (ANG I) locally, thereby accelerating the subsequent tissue production of ANG II (34). In fact, local ANG II generation in the skeletal muscle via nonproteolytic activation of prorenin has been shown to contribute to the development of insulin resistance induced by a high-fructose diet (33). In the present study, we determined whether the prorenin-(P)RR system was involved in insulin resistance and impaired insulin signaling via increased local production of ANG II in the skeletal muscle from HF.…”