Assessment of Candidate Renal Protective Drug-Induced Biomarkers in Diabetic Kidney Disease Using Targeted Proteomic Profiling

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Background: The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin slows the progression of kidney function decline in type 2 diabetes in addition to lowering blood glucose levels. However, the underlying molecular mechanisms of SGLT2i for renoprotection are not yet completely understood. We assessed non-invasive biomarkers associated with empagliflozin or enalapril treatment in a rat model of diabetic kidney disease (DKD). Methods: Obese diabetic and hypertensive ZSF1 rats were treated with vehicle, enalapril (10 mg/kg/d, p.o.), or empagliflozin (30 mg/kg/d, p.o.) for 8 weeks. Along with phenotypic parameters, Olink Mouse Exploratory panel was used to simultaneously detect the levels of 92 proteins in plasma and urine samples using the proximity extension assay. Results: Compared to vehicle and enalapril, empagliflozin reduced blood glucose, HbA1c, total cholesterol, and triglyceride levels while increasing HDL levels in ZSF1 rats. Empagliflozin significantly affected the levels of 16 proteins in plasma samples. Lower plasma concentrations after empagliflozin-treatment were detected for Notch3, tenascin-R, glial cell line-derived neurotrophic factor, and erythropoietin. In urine, we found 23 proteins responding to empagliflozin, 6 of which overlapped with plasma markers. Of these, compared with enalapril, empagliflozin restored the levels of dihydropteridine reductase and dimethylarginine dimethylaminohydrolase 1, proteins known for their role in decreasing ROS activity and oxidative stress. Eight plasma proteins and one urinary protein were found to be differentially expressed after enalapril treatment. Plasma tenascin-R was the only protein associated with both enalapril and empagliflozin treatment. Conclusions: We identified biomarkers that are associated with SGLT2i and ACEi treatment. Our results may additionally provide mechanistic insights into the beneficial effects of renoprotective drugs. Translation and validation of these preclinical findings in human patient samples is the proposed next step. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115974. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA with JDRF. Funding: Commercial Support - Pharmaceuticals, Bayer AG, Wuppertal Germany

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