Ursolic acid reduces inflammation and fibrosis in the kidney of diabetic mice

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UEFISCDI Background Diabetic kidney disease (DKD) is arguably the major disabling and life-threatening microvascular-related disorder associated with both type I and type II diabetes. Inflammation of glomerular capillary system and progressive accumulation of glomerular extracellular proteins are important culprit mechanisms leading to glomerulosclerosis and ultimately renal failure in end-stage DKD. Conventional anti-diabetic therapies can only delay the progression of DKD. The naturally-occurring triterpenic acids emerged as important candidate pharmacological compounds for the treatment of cardiometabolic disorders. Purpose We aimed at investigating the potential regulatory effects of ursolic acid, a pentacyclic triterpenoid, on the expression of key pro-inflammatory and pro-fibrotic mediators in diabetic kidney. Methods Non-diabetic and streptozotocin-induced diabetic C57BL/6J male mice were randomized to receive via intraperitoneal injection 1 mg/kg ursolic acid (UA), or its vehicle (5% DMSO + 95% PBS, pH 7.4), for 4 weeks. Human endothelial cells (EC) were exposed to normal (5 mM) or high (25mM) concentration of glucose in the absence/presence of 1-10 μM UA. Real-time PCR, Western blot, and immunofluorescence microscopy techniques were employed to investigate the expression of selected DKD-relevant pro-inflammatory and pro-fibrotic molecules. Morphological aspects of the kidney and glomeruli were assessed by histochemistry. Results The mRNA/protein levels of pro-inflammatory (MCP-1, TNFα, NOS2, ICAM-1, VCAM-1, E-selectin) and pro-fibrotic (collagen IV, fibronectin, laminin, TGFβ) mediators were found significantly elevated in the kidney of diabetic mice as compared to non-diabetic counterparts. Treatment of diabetic mice with UA significantly reduced the up-regulated expression of pro-inflammatory mediators, extracellular matrix proteins, and pro-fibrotic factor TGFβ. Moreover, glomerular hypertrophy and the up-regulation of glomerular collagen IV, fibronectin, and laminin protein levels were significantly reduced in UA-treated diabetic mice. In cultured human EC, UA suppressed the high glucose-induced up-regulation of ICAM-1, VCAM-1, E-selectin and NF-kB signaling. Conclusion In experimental diabetes, ursolic acid down-regulates the expression of DKD-relevant pro-inflammatory and pro-fibrotic molecules in the kidney of diabetic mice by potentially targeting NF-kB signaling pathway. The data of this study suggest that triterpenic acids and their chemical derivates could become important pharmacological tools to reduce inflammation and fibrosis associated with DKD.