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 characterizes the plasma oxylipins associated with the step-wise progression of DKD. An ultraperformance LC-MS/MS method was performed to quantify 141 kinds of oxylipins in plasma samples of patients with DKD or type 2 diabetes mellitus 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 and receiver-operating characteristic 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. Arachidonic acid (ARA), 5-hydroxyeicosatetraenoic acid (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 the DKD group. The increased plasma levels of ARA, 5-HETE, and 5-oxoETE were strongly correlated with estimated glomerular filtration rate. 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 provides the basis for early identification and therapeutic strategies for DKD.