Hydroxycitric acid inhibits oxalate nephropathies formation through crystallization regulation and activation of the PPARα pathway

Oxalate-induced nephropathies comprise a range of kidney disorders, for which there are no efficient pharmacological treatments. Hydroxycitric acid (HCA) is a derivative of citric acid with a variety of pharmacological activities including reducing body weight and calcium salt deposition. However, the specific mechanism of inhibition of oxalate nephropathies by this compound is not well understood. In this study, we successfully applied bioinformatics-based and simulated drug molecular docking approaches to predict potential targets of HCA. Subsequently, we explored the molecular mechanisms of HCA inhibition of renal calcium oxalate (CaOx) deposition and nephrotoxicity in an oxalate-induced NRK-52E cell model and an oxalate nephropathy rat model. HCA could effectively inhibit CaOx crystal deposition and reduce crystal adhesion and oxidative damage, effectively inhibit lipid deposition caused by high oxalate, and reduce lipid nephrotoxicity. HCA is more effective than traditional stone medications in inhibiting CaOx deposition and kidney damage. Further cellular transcriptomic analysis and in vitro results showed that HCA could stably bind peroxisome proliferator-activated receptor α (PPARα) and promote PPARα-RXR heterodimer formation, thus promoting the expression of downstream oxidative stress molecules (Nrf2, HO-1, SOD) and inhibiting calcium ion release and mitochondrial dysfunction, thus reducing oxalate-induced renal lipid peroxidation damage. Therefore, HCA, a novel drug with the ability to modulate lipid metabolism and inhibit CaOx formation, may be a therapeutic option for the treatment of oxalate nephropathies.