Plasma oxylipin profiling reveals the step-wise activation of ARA/5-HETE metabolism in diabetic kidney disease

Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes concomitant with disordered oxylipin metabolism. Our study characterize the plasma oxylipins associated with the step-wise progression of DKD. An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was performed to quantify 141 kinds of oxylipins in plasma samples of patients with DKD or T2DM and healthy individuals, both in the test cohort (n=40 for each group) and the validation cohort (n=20 for each group). The key oxylipins associated with DKD were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) and receiver-operating characteristic (ROC) curve. Polynomial regression, Pearson's correlation and logistic regression analyses were performed to assess their correlation with the clinical indicators reflecting DKD progression, as well as their diagnostic abilities. Our oxylipin profiling presented the significant alterations of 55 kinds in the test cohort and 42 kinds in the validation cohort. ARA, 5-HETE, 5-oxoETE, 12-HETE and 13(S)-HpODE in the test cohort, as well as ARA, 5-HETE, 5-oxoETE, 20-hydroxyPGF2α and 8,9-EET in the validation cohort were screened as the key oxylipins distinguishing DKD group. The increased plasma levels of ARA, 5-HETE and 5-oxoETE were strongly correlated with estimated glomerular filtration rate (eGFR). The diagnostic model combining the plasma levels of ARA, 5-HETE and 5-oxoETE indicated an excellent diagnostic performance for DKD. Collectively, our study disclosed the profiling of oxylipin metabolism, implicating the activation of ARA/5-HETE metabolism associated with the step-wise progression of DKD, which provide the basis for early identification and therapeutic strategies for DKD.