Objectives: Obesity is major worldwide health problem, and can be related to cellular senescence. Along with the rise in obesity, the comorbidity of renal ischemia-reperfusion (IR) injury is increasing. Obesity may accelerate the severity of IR injury, but whether senescence contributes to these conditions remains unclear. We studied cellular senescence in IR kidneys and perirenal adipose tissues of high-fat-diet-induced obese mice.   Methods: C57BL/6 mice fed standard chow or high-fat diet for 16 weeks were randomized to renal IR or sham (n=6-10, each). Renal IR was performed by unilateral clamping of the right renal pedicle for 30 minutes. After 6 weeks of surgery, renal function, perirenal fat/renal senescence, and histology were evaluated ex vivo.   Results: Final body weight of mice fed a high-fat diet was approximately twice that of the control groups. The ratio of right to left kidney was decreased in IR compared to sham groups, but was similar between control-IR and high-fat diet-IR. The degree of renal tubular injury, fibrosis, and inflammation was higher in high-fat diet-IR than in control-IR (Fig. 1). Renal gene expressions of senescence and its secretory phenotype were upregulated in control-IR and high-fat diet-sham compared to control-sham. Moreover, expression of Cdkn1a, Tgfb1, and Serpine1 further increased in IR kidneys of high-fat diet mice. Expression of Cdkn1a gene and senescence-associated β-galactosidase was higher in both abdominal and perirenal adipose tissues of high-fat diet mice than in the control, whereas IL-6 and TNFα gene and protein levels were increased only in the perirenal depot (Fig. 2). Conclusions: High-fat diet aggravates ischemia-reperfusion injury in murine kidneys, which may be related to perirenal fat cellular senescence induced by obesity. These observations support exploration of senolytic strategies in the adipo-renal axis of obesity.