397-P: Epigenetic Regulation of the Chemokine CXCL2 in Acute Kidney Injury in Diabetes

People with diabetes are much more likely to develop acute kidney injury (AKI) than people who do not have diabetes. Here we took a reverse translational approach to identify factors that increase the risk of AKI in diabetes. Aged diabetic high fat diet-fed (DM-HFD) mice and nondiabetic controls were randomized to sham or bilateral renal ischemia reperfusion injury (IRI) surgery, with phenotyping performed 24h later. DM-HFD mice with IRI had increased plasma BUN and creatinine and increased tubule injury in comparison to either nondiabetic mice with IRI or DM-HFD mice that underwent sham surgery. NanoString nCounter analysis of AKI kidneys revealed that 47 of 248 inflammatory genes were differentially expressed in the kidneys of DM-HFD IRI mice in comparison to nondiabetic mice with IRI. The top hit was the chemokine Cxcl2, which was upregulated 2429-fold compared with sham-operated nondiabetic mice and 92-fold compared with nondiabetic mice with IRI. Urine CXCL2 excretion was increased >200-fold in DM-HFD IRI mice. By RNAscope in situ hybridization, Cxcl2 was observed to be upregulated in DM-HFD IRI kidneys, being localized primarily to infiltrating inflammatory cells, but also expressed in glomeruli and scattered tubule epithelial cells. Stimulation of bone marrow-derived macrophages (BMDMs) with lipopolysaccharide caused release of CXCL2 into the culture medium, with a significant increase in CXCL2 secretion by BMDMs from mice with myeloid cell deletion of the histone demethylase KDM6A (LysMCre+Kdma6fl/ymice). In summary, augmented AKI in aged diabetic high fat diet-fed mice is accompanied by upregulation of the myeloid cell chemoattractant CXCL2, which itself is under the influence of the histone demethylating enzyme KDM6A. The findings provide insights into the molecular causes of worsened AKI in diabetes and they illustrate that, like chronic kidney disease in diabetes, AKI processes in diabetes are also under epigenetic regulation. Disclosure S. Batchu: None. V. Yerra: None. Y. Hong: None. P. Plant: None. Y. Liu: None. A. Advani: None. Funding Canadian Institutes of Health Research (PJT166083 to A.A.)