Maresin-1 ameliorates renal oxidative stress and inflammation in diabetic kidney disease mice partially dependent on apolipoprotein D upregulation.

Diabetic kidney disease (DKD) is a prevalent diabetic microvascular complication driven by persistent, unresolved renal inflammation, while specialized pro-resolving mediators (SPMs) represented by Maresin-1 (MaR1) have emerged as promising candidates against DKD. This study investigated whether apolipoprotein D (APOD) acts as a critical downstream mediator of MaR1. A mouse model of type 2 diabetic kidney disease was established using a high-fat diet combined with streptozotocin. In vivo pharmacologic intervention and in vitro high glucose-induced HK2 cell culture combined with proteomic screening, pathological staining, multiple molecular detection and APOD gain/loss-of-function assays were sequentially performed. Exogenous MaR1 treatment significantly ameliorated metabolic and renal dysfunction in DKD mice lowing random blood glucose after week 26 and markedly reducing the urine albumin-to-creatinine ratio (UACR) by approximately 30%. MaR1 intervention also effectively attenuated renal fibrosis. As expected, MaR1 suppressed renal and HG-induced tubular pro-inflammatory cytokines (IL-1β, TNF-α, and IL-18) while upregulating protective IL-10 levels. Proteomic screening, combined with qPCR, Western blot, and immunofluorescence, confirmed that renal APOD expression was elevated 1.5-fold in DKD mice. In HK2 cells, APOD silencing via siRNA completely abolished MaR1-mediated suppression of ROS and pro-inflammatory cascades. Conversely, APOD overexpression successfully mimicked and synergistically enhanced the anti-inflammatory and antioxidant actions of MaR1. In conclusion, MaR1 alleviates renal oxidative injury and inflammation in a manner partially dependent on tubular APOD upregulation, highlighting the MaR1-APOD axis as a novel prospective therapeutic target for DKD intervention.