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.