Renometabolic disorder in experimental rat model of polycystic ovarian syndrome is reversed by acetate-mediated inhibition of pyruvate dehydrogenase kinase 4

Abstract

BACKGROUND: Chronic Kidney disorders is a global public health problem, including in women with polycystic ovarian syndrome (PCOS), and is characterized by renal fibrosis, nephrotoxicity and glomerulonephritis, which increases the possibility of renal failure and organ transplant. Pyruvate dehydrogenase kinase 4 (PDK4) has been implicated in mitochondria dysfunction, contributing to metabolic dysregulation in different organs, including kidney. Studies have shown that short chain fatty acids, particularly acetate, alleviates metabolic alterations in experimental models. Hence, the present study investigated the therapeutic potential of acetate on renometabolic disorders associated with experimental PCOS model. The study in addition elucidates the probable involvement of PDK4 in PCOS-associated renometabolic disorders. METHODS: Eight-week-old nulliparous female Wistar rats were randomly allotted into four groups (n = 5). Letrozole (1 mg/kg bw) was used to induce PCOS for 3 weeks. Thereafter, acetate (200 mg/kg bw) was administered for 6 weeks, uninterruptedly. Biochemical parameters from the plasma and renal tissue, as well as histology of ovaries were performed with appropriate methods. RESULTS: Experimental PCOS rats were characterized with elevated circulating testosterone and the presence of multiple ovarian cysts. In addition, rat with PCOS also manifested insulin resistance, increased plasma urea and creatinine levels, increased renal Gamma glutamyl transferase (GGT), malondialdehyde (MDA), Nuclear factor -kappa B (NF-kB), Tumor necrosis factor -alpha (TNF-a), Transforming growth factor -beta 1 (TGF-B1), caspase-6, Histone deacetylase 2 (HDAC2), while a decrease in glucose-6 phosphate dehydrogenase (G6PD), reduced glutathione (GSH), renal nitric oxide (NO) and endothelial nitric oxide synthesis (eNOS), when compared with animals in the control group. These were associated with elevated level of PDK4 in the renal tissue. However, administration of acetate ameliorates these renal/metabolic abnormalities. CONCLUSION: Altogether, the results from the present study suggests that acetate ameliorates renal dysfunction in PCOS via downregulation of PDK4.