Adonesine A1 receptor and megalin defect in diabetic mice with early kidney disease

Abstract

Objective To observe the effect of adenosine A1 receptor (A1AR) on the megalin defect in type 1 diabetic mice with early kidney disease. Methods 7-8 week-old, baseline body weight and fasting blood glucose matched wild type (WT) C57BL/6J mice were selected, and randomly divided into two groups: control group (n=6) and WT DM group (n=6). In the same way, male A1AR knock-out C57BL/6J mice were selected as A1AR-/- DM group (n=6). DM model was established by intraperitoneal injection of streptozocin. The blood glucose (BG), body weight (BW), kidney weight (KW), 24 h proteinuria (24hUP) and albumin creatine ratio (ACR) were measured at 4 weeks. The renal pathological lesion was observed and the expression of megalin in proximal tubules was examined by immunohistochemistry. The expression of caspase-1, IL-18 and A1AR were detected by Western blotting. Results At 4th week, compared with WT control mice, the BG, BW, KW and 24hUP of WT DM mice were increased significantly (n=6, P<0.01), with the pathological glomerular enlargement, mesangial cell proliferation, extracellular matrix accumulation and renal tubule hypertrophy being observed. Immunohistochemistry revealed decreased expression of megalin, an important multiligand protein receptor on the brush border of proximal tubular epithelial cells in WT DM mice, which was correlated with 24hUP (r=-0.645, P<0.01). Compared with the control mice, the expressions of caspase-1, IL-18 and A1AR were significantly increased in WT DM mice (P<0.05). For A1AR-/- DM mice, more serious pathological lesion and megalin defect, together with increasing of casapase-1 and heavier proteinuria were observed than those in WT DM mice. Conclusion A1AR may play a protective role in megalin expression of diabetic mice with early kidney disease, in which the mechanism may be associated with caspase-1 related pyroptosis pathway. The details need further exploration. Key words: Diabetic nephropathies; LDL-receptor related protein 2; Receptor, adenosine A1; Caspase-1