Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular and renal diseases but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits oxidative stress and albuminuria in streptozotocin (STZ)-induced type 1 diabetes mellitus rats, via a protein kinase A (PKA)-mediated inhibition of renal NAD(P)H oxidases. Diabetic rats were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Oxidative stress markers (urinary 8-hydroxy-2'-deoxyguanosine and renal dihydroethidium staining), expression of renal NAD(P)H oxidase components, transforming growth factor-β (TGF-β), fibronectin and urinary albumin excretion were measured. In vitro effect of liraglutide was evaluated using cultured renal mesangial cells. Administration of liraglutide did not affect plasma glucose levels or body weights in STZ diabetic rats, but normalized oxidative stress markers, expression of NAD(P)H oxidase components, TGF-β, fibronectin in renal tissues and urinary albumin excretion, all of which were significantly increased in diabetic rats. In addition, in cultured renal mesangial cells, incubation with liraglutide for 48 h inhibited NAD(P)H-dependent superoxide production evaluated by lucigenin chemiluminescence in a dose-dependent manner. This effect was reversed by both PKA inhibitor H89 and adenylate cyclase inhibitor SQ22536, but not by Epac2 inhibition via its small interfering RNA. Liraglutide may have a direct beneficial effect on oxidative stress and diabetic nephropathy via a PKA-mediated inhibition of renal NAD(P)H oxidase, independently of a glucose-lowering effect.

No abstract

Aims/Introduction:  Diabetic cardiomyopathy entails the cardiac injury induced by diabetes, independent of vascular disease or hypertension. Despite numerous experimental studies and clinical trials, the pathogenesis of diabetic cardiomyopathy remains elusive. Here, we report that chymase, an immediate angiotensin II (AngII)‐forming enzyme in humans and hamsters, and NOX4‐induced oxidative stress have pathogenic roles in myocardial fibrosis in diabetic hamsters.Materials and Methods:  Expression of chymase was evaluated in the hearts of streptozotocin (STZ)‐induced diabetic hamsters. The impact of chymase‐specific inhibitors, TEI‐E00548 and TEI‐F00806, on myocardial fibrosis, and increased levels of intracardiac AngII, accumulation of 8‐hydroxy‐2′‐deoxyguanosine (an oxidative stress marker in urine and heart tissue) and expression of heart NOX4 in diabetic hamsters were investigated.Results:  Myocardial chymase expression was markedly upregulated in STZ hamsters in a glucose‐dependent manner. A total of 8 weeks after STZ administration, the diabetic hamsters showed enhanced oxidative stress and NOX4 expression in the heart, in parallel with increased myocardial AngII production. Oral administration of chymase‐specific inhibitors, TEI‐F00806 and TEI‐E00548, normalized heart AngII levels, and completely reversed NOX4‐induced oxidative stress and myocardial fibrosis in STZ‐induced diabetic hamsters, although they did not affect the activity of the systemic renin–angiotensin system or systolic blood pressure.Conclusions:  Chymase inhibition might prevent oxidative stress and diabetic cardiomyopathy at an early stage by reducing local AngII production. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00202.x, 2012)

Length of hospital stay, hospital cost, and MR were higher in elderly with CAH. Female gender, hydrochlorothiazides, loop diuretics, and ≥2 comorbid diseases are the leading risk factors associated with CAH in elderly.