Empagliflozin and linagliptin ameliorate podocyte injury and enhance autophagy in a model of type 2 diabetic nephropathy

Podocyte injury is believed to be a cornerstone in pathogenesis of diabetic kidney disease. Recent data indicate emerging role of autophagy downregulation in diabetic podocytopathy. Inhibitors of SGLT2 and DPP4 are considered as promising therapeutic agents in diabetic nephropathy. We aimed to assess the effects of SGLT2 inhibitor empagliflozin and DPP4 inhibitor linagliptin on podocyte injury and autophagy in a model of type 2 diabetes. Eight-week-old male db/db mice were treated with empagliflozin (10 mg/kg), linagliptin (10 mg/kg), combination of these agents, or placebo for 8 weeks. Non-diabetic db/+ mice were acted as control. Renal changes were analyzed from the light and electron microscopy. To estimate autophagy, beclin-1 staining in glomeruli and the number of autophagosomes, lysosomes, and autolysosomes in a section of a podocyte were assessed by immunohistochemistry and electron microscopy, respectively. Diabetic db/db mice became obese and hyperglycemic before the start of experiment and demonstrated elevated levels of leptin and insulin and increased fat percentage (all p<0.00001). Vehicle-treated diabetic mice had weak staining for beclin-1 in glomeruli and reduced autophagosome number in podocytes. Beclin-1-positive area correlated with the number of autophagosomes and lysosomes (both r=0.43, p=0.04) and mean width of foot processes (r=-0.64, p=0.0008). Under the treatment, glomerular staining for beclin-1 was increased (p=0.03 for empagliflozin, p=0.008 for linagliptin, p=0.003 for combination). Empagliflozin and linagliptin, either alone or both, increased the number of autophagosomes (p=0.04) and autolysosomes (p=0.03) in podocytes. The data provide further explanation for the mechanism of nephroprotective effect of SGLT2 and DPP4 inhibitors in diabetes.