Disrupted renal clock and blood pressure rhythms in type 2 diabetic nephropathy

Type 2 diabetes mellitus (T2DM), accounting for approximately 90% of adult-onset diabetes cases, is a major risk factor for diabetic kidney disease (DKD). Emerging evidence has linked T2DM with disrupted circadian rhythms. However, its role in the progression of DKD remains poorly understood. To investigate the relationship between circadian rhythms and DKD, we used the type 2 diabetic nephropathy (T2DN) rat, a non-obese model that replicates key features of human DKD. Circadian rhythms were assessed in both male and female T2DN rats at 20 and >35 weeks (young and old) by continuous measurements of mean arterial pressure (MAP), systolic blood pressure (SBP), heart rate, and locomotor activity. Differential expression of circadian genes was evaluated by RNA sequencing of kidney cortex. In separate cohorts, the effects of renal denervation and melatonin treatment on circadian parameters were examined. T2DN rats exhibited impaired circadian rhythms in MAP and SBP, while heart rate and locomotor activity retained rhythmicity. Transcriptomic analysis revealed altered expression of several circadian-related genes, including core circadian gene Per1 and multiple circadian-controlled genes involved in insulin sensitivity, lipid metabolism, and immune regulation between different groups of T2DN rats. Neither renal denervation nor melatonin administration restored normal circadian rhythms of T2DN rats. Our data suggest that circadian rhythm disruption of blood pressure is a consistent feature of T2DN rats and that targeting circadian clock components such as Per1 could offer potential therapeutic strategies.