Adiponectin is one of the numerous bioactive substances known as adipokines produced by adipose tissue. Adiponectin is considered to interplay with other adipokines to exert the milieu of metabolic syndrome. It binds to adiponectin receptors (AdipoR), AdipoR1 and AdipoR2 and exhibits antidiabetic effects via activation of AMPK and PPAR-α pathways. Orally active synthetic small-molecule AdipoR agonist, AdipoRon binds to both AdipoR1 and AdipoR2 in vitro and ameliorates obesity-related disease such as type 2 diabetes. Besides, it has been suggested that adiponectin confers renoprotective effects in diabetes. Therefore, we investigated the possible role of AdipoRon in renal physiology in the view of prevention and development of diabetic nephropathy in diabetic mouse model. Male db/db mice and db/m controls were fed either a regular diet chow or a diet containing AdipoRon (30 mg/kg/day p.o. for 4 weeks from 17 to 20 weeks of age). Serum, urine and renal tissue specimen were obtained to analyze for changes in metabolic parameters, relevant molecular levels and their association with regard to structural influence. AdipoRon fed db/db mice showed decreased amount of albuminuria with no significant changes in the levels of serum adiponectin, glucose and creatinine and it seems to be weight neutral. In the molecular level, increased expressions of AdipoR1 and AdipoR2 in the renal cortex, more preferentially AdipoR1, were observed in db/db mice with AdipoRon administration. Consistent up-regulations of phophorylated AMPK and PPAR-α level were associated within the same group. With respect to ultrastructure, AdipoRon treatment showed favorable effects on diabetes-induced GBM thickening, foot process widening and slit diaphragm space narrowing, further decreasing glomerular matrix expansions and inflammation. Increased expressions of renal AdipoR1and AdipoR2 levels indicate that renal injury may cause a compensatory up-regulation of relevant receptors in kidneys to mitigate further renal injury. AdipoRon may control oxidative stress in glomerulus through AMPK and PPAR-α activated pathways and further contribute to prevent deterioration of renal function. The protective role of AdipoRon against the development of albuminuria seems to occur through a direct action on podocytes independently of systemic effects of adiponectin. Its reduction of oxidative stress provides protection against albuminuria and podocyte damage thereby ameliorating endothelial dysfunction.