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. Here, we used the type 2 diabetic nephropathy (T2DN) rat, a non-obese model that replicates key features of human DKD, to investigate the relationship between circadian rhythms and 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), heart rate, and locomotor activity. Differential expression of circadian genes was evaluated by RNA-sequencing of the kidney cortex. In separate cohorts, the effects of renal denervation and melatonin treatment on circadian parameters were examined. Results indicated that T2DN rats exhibited disrupted circadian rhythms in MAP, with males showing a significant presence of a non-dipping phenotype (115 +/- 0.7 mmHg vs 117 +/- 1.0 mmHg, day vs night, young male; 110 +/- 0.8 mmHg vs 111 +/- 1.0 mmHg, day vs night, old male). In contrast, heart rate and locomotor activity retained rhythmicity and dipping patterns. Transcriptomic analysis revealed altered expression of core circadian gene Per1 (Log2FC=-1.0, old male vs old female) 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. In summary, our results suggested that disrupted circadian rhythm may contribute to DKD progression, and differential expression of Per1 may serve as a potential molecular mechanism linking circadian dysregulation to kidney injury in T2DM. Funding sources: National Institute of Health Grants R01 DK 135644 (to AS), R01 DK129227 (to AS and OP), and K99 DK143296 (to BX), AHA Career Development Award 25CDA1449142 (to MS), and USF Hypertension Kidney Research Center Early Investigator Awards (to RT and OK). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Xu et al. (Fri,) studied this question.