Melatonin Mitigates High-Calorie Diet-Induced Obesity-Related Glomerular and Tubulo-interstitial Injury in Rats

Background: The kidney is a primary target for obesity-related damage due to its role in compensating for metabolic disturbances caused by excess fat tissue accumulation. Melatonin - a universal adaptogen - emerged as a promising candidate for mitigating obesity-induced kidney injury. Circadian rhythms play a crucial role in the regulation of kidney function, influencing processes such as filtration, reabsorption, and electrolyte balance, and evidence suggests that melatonin, through its ability to normalize disrupted circadian rhythms, may support kidney health. We hypothesized that melatonin will ameliorate obesity-related kidney injury. Methods: The study was conducted on outbred Wistar male rats weighing 110±10 g randomly assigned into groups (N≥5/group). Obesity was induced by a high-calorie diet (HCD) (38.8% fat, 15.5% protein and 45.7% carbohydrate) for 6 weeks ad libitum (HCD was based on control Purina VITA chow (6.7% fat, 21% protein and 55.1% carbohydrate)). Vehicle or melatonin (~30 mg/kg) were administered for 7 weeks in drinking water ( ad libitum ); the following 4 groups were studied: control (lean), HCD, HCD+Melatonin (HCD+M) and lean+Melatonin (C+M). Assessment of renal damage with PAS, Masson’s trichrome, Picrosirius Red, and IHC for kidney injury molecule-1 (KIM-1) was conducted by a pathologist. Statistical analysis was performed in OriginPro (2-way ANOVA, factors: diet and treatment, Tukey post hoc test). Results: Compared to lean group, HCD animals exhibited a significant increase in the relative visceral fat (1.8±0.1 vs. 2.9±0.3% for lean vs. HCD, p<0.05) and visceral adipose levels of resistin (100±2 vs 128±3% lean vs. HCD, p<0.05). Importantly, melatonin resulted in a significant attenuation of obesity parameters (2.9±0.3 vs. 1.8±0.2% for relative visceral fat, and resistin 128±3 vs. 108±2.2% for HCD vs. HCD+M, respectively, p<0.05). Kidney hypertrophy (as indicated by kidney weight) was exacerbated in the HCD group compared to the control (1.95±0.1 vs. 2.7±0.1 g for lean vs. HCD, p<0.05); a trend for an attenuation in the HCD+M group was observed which did not reach statistical significance (2.0±0.1, 2.7±0.1, and 2.3.±0.1 g for lean, HCD, and HCD+M, correspondingly; p=0.1). In obese rats, melatonin administration decreased glomerulomegaly by 17% (16.3±0.5 vs. 13.5±0.4 x10 3 μm 2 , HCD vs. HCD+M, p<0.05). The fibrosis level in the HCD+M group was also decreased (10.2±0.5 vs. 4.6±0.4 % relative area, HCD vs. HCD+M, p<0.05). The KIM-1 level in HCD+M treatment was 35% lower compared to the HCD group, and proximal tubular (PT) damage indicated a significant improvement in HCD+M group (0.53±0.11 vs.1.33±0.14, and 0.8±0.08 a.u. for KIM-1 staining, and 0.3±0.1 vs. 2.1±0.3 and 1.1±0.2 PT damage score, in lean vs. HCD, and HCD+M, respectively; p<0.05). Conclusions: Continuous administration of melatonin leads to significant improvement of renal lesions without no marked side effects in lean rats. In ongoing studies, we are testing the mechanistic impact of melatonin administration on the kidney clock and its role in the mitigation of obesity-related damage. The research was supported by AHA International Visiting Professorship Award 24IVPHA1293598 (to OK and OP) and AU Physiology startup funds (to DVI) This abstract was presented at the American Physiology Summit 2025 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.