Sex-specific effects of metformin and liraglutide on renal pathology and expression of connexin 45 and pannexin 1 following long-term high-fat high-sugar diet.

The comparative effects of the two commonly used antidiabetic drugs metformin and liraglutide on renal pathology and expression of connexin 45 (Cx45) and pannexin 1 (Panx1) in adult obese rats fed high-fat high-sugar diet (HFHSD) were studied. Considering recent data on the profound influence of sex on metformin and liraglutide effects, we compared the effects of both drugs between male and female animals. 44-week-old Sprague-Dawley rats were separated into 4 groups that were fed: standard diet, HFHSD, HFHSD treated with metformin (s.c., 50 mg/kg/day) and HFHSD treated with liraglutide (s.c., 0.3 mg/kg/day). Treatment with metformin or liraglutide lasted for 14 weeks. Histology and immunohistochemistry were performed to quantify renal pathological changes and Cx45 and Panx1 expression. HFHSD caused thickening of the Bowman's capsule (BC). Both metformin and liraglutide failed to ameliorate the BC thickening; metformin even worsened it. Effects on the tubulointerstitial fibrosis score, BC thickness and Cx45 and Panx1 expression were sex-dependent. We found a 50% increase in mitochondria in proximal tubules of metformin- and liraglutide-treated HFHSD-fed rats, but these effects were not dependent on the sex. This is a first study showing that the effects of metformin and liraglutide on kidney pathology in rats fed HFHSD are mostly sex-dependent and that these effects are not necessarily beneficial. Both drugs changed the Cx45 and Panx 1 expression; hence their effects could be related to amelioration of disruptions in intercellular communication.

PUFAs supplementation affects the renal expression of pannexin 1 and connexins in diabetic kidney of rats.

In diabetic nephropathy (DN), intercellular communication is disrupted. Connexins (Cx) have a crucial role in that process. Dietary ratios and supplementation with polyunsaturated fatty acids (PUFAs) can alleviate diabetic complications and cause alterations in Cx levels. Although pannexins (Panx) share similarities with members of the Cx family, their function in diabetic nephropathy has still not been fully determined. We studied the influence of PUFA supplementation on the immunoexpression of Px1 and Cx family members in diabetic kidneys of rats. Four groups of rats in experimental DM1 model were supplemented with different dietary n-6/n-3 ratios; ≈7 in control (C) and diabetic groups (STZ), ≈ 60 in the STZ + N6 group and ≈ 1 (containing 16% EPA and 19% DHA) in the STZ + N3 group. Immunoexpression of Cx40, Cx43, Cx45 and Panx1 was evaluated in the renal tissue of diabetic rats using immunohistochemistry. Diabetes significantly decreased the protein expression of Cx40 and Cx43 and increased Panx1 protein expression in the renal cortex (p < 0.05-p < 0.01). There was a significant impact of diet on Cx and Panx1 immunoexpression. Dietary supplementation with a high n-6/n-3 ratio downregulated the protein expression of Cx45 and Panx1 in diabetic rats (p < 0.05-p < 0.01), while Cx43 immunoexpression was increased in diabetic rats fed with high and low n-6/n-3 ratios (p < 0.01-p < 0.001). Hyperglycaemic conditions in DN interfere with cell-to-cell communication and disturb the connection between cells and their immediate environment due to variations in connexin and pannexin immunoexpression. These variations can be regulated by PUFA dietary intake, suggesting their beneficial effect and possible therapeutic option.