Effects of pemafibrate, a selective PPARα agonist, on abnormal renal energy metabolism in diabetic kidney disease.

The global number of patients with diabetes has reached 420 million, and the prevalence of diabetic kidney disease (DKD) is rising steadily. DKD is a serious complication of diabetes, making up about 40% of the underlying condition in patients on chronic dialysis. In recent years, several randomized controlled trials have confirmed the reno-protective effects of SGLT2 inhibitors in patients with DKD (DeFronzo, et al. Nat Rev Nephrol. 2021). Altered renal energy metabolism has been reported as a possible mechanism behind this effect (Schaub, et al. J Clin Invest. 2023), and the pathophysiological significance of renal energy metabolism in DKD has gained attention. A major obstacle to DKD research progress has been the lack of animal models that accurately reflect the clinical features of human DKD (Azushima, et al. Nat Rev Nephrol. 2018). Previous DKD mouse models mostly reproduce early-stage DKD characteristics, such as mild albuminuria and mesangial expansion, with few models showing features of advanced DKD. Recently, we successfully developed a novel advanced DKD mouse model by inducing type 1 diabetes with streptozotocin (STZ) in systemic angiotensin II (Ang II) type 1 receptor (AT1R) associated protein (ATRAP, an endogenous suppressor of AT1 R signaling pathway) deficient mice, followed by continuous Ang II administration. This model exhibited severe albuminuria, worsening renal histology, and progressive renal dysfunction (Taguchi et al. Hypertens Res. 2024). In this study, using our advanced DKD model mice, we aim to explore the significance of renal energy metabolism disorders in DKD with a focus on fatty acid oxidation and lactate metabolism.

Ten-week-old C57BL/6J control mice (WT) and systemic ATRAP deficient mice (KO) were used. The WT group received vehicle for consecutive five days, while the KO group received STZ at a dose of 55 mg/kg for consecutive five days. Four weeks later, blood glucose was measured, and mice with a none-fasting glucose level of 288 mg/dL or higher were placed in the DM group. The diabetic KO group was further divided into three groups: a normal diet group, a low-dose pemafibrate diet group, and a high-dose pemafibrate diet group. All KO groups received continuous angiotensin II (1000 ng/kg/min) infusion via osmotic pumps for 6 weeks. At 20 weeks of age, mice were dissected, and their tissues were evaluated. As physiological parameters, body weight, blood pressure, blood glucose, and 24-hour urinary albumin excretion were measured at 14 and 20 weeks of age. Renal histological changes, including degree of glomerular and tubulointerstitial damage, were also assessed.

Preliminary studies indicated that the phosphorylated AMPK/AMPK ratio, an indicator of energy stress in the organ, was significantly decreased in the kidneys of the DKD model mice compared to non-diabetic WT control mice. Additionally, gene expression of the LDHA/LDHB subunits of lactate dehydrogenase (LDH), an enzyme involved in glycolysis that catalyzes the conversion of pyruvate to lactate, was elevated. Changes in gene expression of PPARα, CPT1, and other genes related to fatty acid oxidation were also observed.

Experiments are still in progress, and the results of this study, including effects of the PPARα agonist on DKD will be presented at the upcoming general meeting.