Liraglutide attenuates renal tubular ectopic fat deposition in diabetic nephropathies rats through inhibiting sterol regulatory element binding protein 1

Abstract

Objective To investigate the effect and mechanism of liraglutide on ectopic fat deposition in rats with diabetic nephropathies (DN). Methods Forty male SD rats were randomly divided into three groups: normal control rats group (n=10), DN vehicle control rats group (n=15) and DN rats with liraglutide group (n=15). DN rats received subcutaneous injection of liraglutide (0.4 mg·kg-1·d-1) for 12 weeks. Body weight, 24 h urine volume, 24 h total urine protein, serum insulin level, blood glucose, serum triglyceride (TG), total cholesterol (TC), and other biochemical index were detected after 12 week treatment of liraglutide. The histopathological changes of rat kidney were evaluated by periodic acid-schiff staining. The protein expression, distribution of sterol regulatory element binding protein and adipose differentiation-related protein in rat kidney were detected with immunohistochemistry. Renal tissue adenosine monophosphate activated protein kinase (AMPK), sterol regulatory element binding protein 1 (SREBP-1), adipose differentiation related protein (ADRP), fatty acid synthase (FAS) and p-AMPK phosphorylation levels protein expression in rats kidney were examined using western blot. One-way ANOVA was used to compare groups, pairwise comparison was tested by the least significant difference method. Results Compared to normal control group, the blood glucose, 24 h urine volume, and 24 h total urinary protein levels were increased in the DN vehicle control group (t=8.630-28.251, all P<0.01). When treated with liraglutide for 12 weeks, the total urine protein content of the DN vehicle control rats group was significantly higher than that of the diabetic rats before modeling [(20.3±10.6) vs (5.9±2.0) g/24 h, t=3.965, P<0.01]. Glomerular mesangial cell proliferation and matrix expansion, serum TG and TC was significantly increased (t=3.616, 2.363, all P<0.05) . SREBP-1 and ADRP proteins were mainly distributed in tubular (t=7.588, 6.160, all P<0.01) , and proteins expression of SREBP-1, FAS and ADRP protein in kidney tissue increased significantly, while AMPK phosphorylation levels in kidney tissue decreased (t=6.122,8.78,11.16, -12.78, all P<0.01). Compared to DN vehicle control group, the body weight of DN rats decreased significantly after 12 weeks of treatment with liraglutide, serum TG and TC decreased significantly (t=-3.338, -2.944, -2.390, all P<0.05). SREBP-1, FAS, ADRP protein expression in rats kidney was significantly decreased, while the phosphorylation level of AMPK in renal tissue was increased (t=-2.833, -4.228, -11.850, 7.653, all P<0.05). Conclusion Liraglutide inhibits renal ectopic fat deposition in rats with DN, which may be related to the increase of AMPK phosphorylation activity, inhibition of SREBP-1 transcriptional activity, reduction of FAS expression and subsequent inhibition of fatty acid synthesis pathway by liraglutide. Key words: Diabetic nephropathies; Fatty acid synthesis; Sterol regulatory element-binding proteins; Liraglutide