Transcriptomic Exploration of Tetrahydrocurcumin Effects in Chronic Kidney Disease.

Introduction: Chronic kidney disease (CKD) involves a progressive loss of renal function and is characterized by chronic oxidative stress and kidney fibrosis. Tetrahydrocurcumin (THCu), a metabolite of curcumin, may possess antioxidant benefits in CKD. This study evaluated the transcriptomic changes and therapeutic potential of THCu against kidney damage and fibrosis in the 5/6 nephrectomy rat CKD model. Methods: Adult female Sprague-Dawley rats were randomized into CKD groups and three THCu doses were tested (100, 300 and 500 mg/kg). A liposomal formulation of THCu was given twice daily via oral gavage for 4 weeks. Serum creatinine and proteinuria were measured, and kidney fibrosis was assessed on histology. Kidney lysates were processed for total RNA sequencing to analyze differential gene expression in the experimental groups. The data were screened for outliers prior to ANOVA and correlation analyses. Results: In the untreated CKD group, serum creatinine and proteinuria were increased compared to control animals. Transcriptomic profiling revealed that untreated CKD animals exhibited marked upregulation across three key gene categories: immune cell activation, kidney injury and fibrosis, and inflammation and oxidative stress. THCu treatment mitigated these pathways by which there was downregulation of markers of immune cell activation as well as the kidney injury marker Kim1, while the fibrosis markers Col1a1 and Col3a1 were decreased to expression levels similar to non-CKD control animals. Furthermore, the highest dose of THCu at 500 mg/kg triggered a cellular detoxification and metabolic clearance response, with highly significant upregulation of Abcb11 and Gls2. Antioxidant benefit was evidenced by upregulation of Gpx1 in the high-dose THCu group compared to the untreated CKD group. Pathway enrichment analysis demonstrated that the high-dose THCu group restored key metabolic and signaling pathways disrupted in renal fibrosis, including small and organic solute metabolism, fatty acid oxidation, lipid biosynthesis, and peptide hormone response. Furthermore, the treatment upregulated essential anion and organic solute transport functions. Proteinuria was reduced with THCu therapy; however, serum creatinine and urine creatinine clearance were not significantly modified in comparison to untreated CKD rats. Conclusions: Oral THCu therapy demonstrated promising transcriptional changes in antioxidant and anti-fibrotic pathways in a rat CKD model. Confirmatory protein-level studies are needed to clarify benefits on kidney function.