Boeravinone C ameliorates lipid accumulation and inflammation in diabetic kidney disease by activating PPARα signaling

Ethnopharmacological relevance The roots of Oxybaphus himalaicus Edgew. is a traditional Tibetan herbal medicine with kidney reinforcing and tonifying effects, which is commonly applied to treat nephritis. Boeravinone C has been identified as one of the primary constituents of O. himalaicus. However, the potential renal protective effects of boeravinone C remains unclear. Aim of the study This research aimed to investigate the protective effects of boeravinone C on diabetic kidney disease and the underlying mechanisms. Materials and methods Streptozotocin (100 mg/kg) was intraperitoneally injected to induce DKD in mice. High glucose (50 mM)-induced HK-2 cells were utilized to investigate the mechanisms of boeravinone C against tubular injuries in vitro . Anti-DKD activity was assessed by measuring reactive oxygen species (ROS) levels, analyzing apoptosis through flow cytometry, and evaluating inflammation, apoptosis, and FAO-related proteins via Western blotting. Additionally, serum biochemical assays, as well as histopathological and immunohistochemical analyses of kidney tissues, were performed to explore the pharmacological effects of boeravinone C. Results In vivo , boeravinone C administered significantly reduced the creatinine (CRE), blood urea nitrogen (BUN), triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels in serum of DKD mice. In vitro , boeravinone C significantly restored the apoptosis induced by HG in HK-2 cells, which is further validated by an upregulation of the apoptosis-inhibiting protein Bcl-2, along with a decreased expression of the apoptosis-promoting proteins Bax and caspase-3. Mechanistically, boeravinone C reversed HG-induced downregulation of peroxisome proliferator-activated receptor α (PPARα) expression. As a transcription factor, elevated expression of PPARα led to upregulation of CPT1A and ACOX1, which then enhanced fatty acid oxidation (FAO) to reduce lipid accumulation in HK-2 cells. Furthermore, boeravinone C-mediated high expression of PPARα sequestered p65 subunit of NF-κB in the cytoplasm, leading to reduced expression of proinflammatory cytokines such as iNOS, TNF-α and IL-6. To verify that the therapeutic effects of boeravinone C in diabetic kidney disease (DKD) are mediated via PPARα activation, we developed a PPARα knockdown HK-2 cell line. Our findings revealed that PPARα downregulation modified biological effects of boeravinone C, especially regarding fatty acid metabolism and the inflammatory response, with significant repercussions on apoptosis. Conclusion This study demonstrates that the major component boeravinone C from O. himalaicus promotes the fatty acid oxidation and suppresses inflammatory response by upregulating PPARα expression, thereby reducing apoptosis in HG-induced renal tubule cells. Consequently, boeravinone C restores tubular function in DKD mice. Collectively, this study provides a pharmacological basis for utilizing of O. himalaicus in treating DKD.