Renal Lipid Alterations From Diabetes to Early‐Stage Diabetic Kidney Disease and Mitophagy: Focus on Cardiolipin

Lipotoxicity plays a crucial role in the progression of diabetic kidney disease (DKD), yet the dynamic changes in renal lipid composition from diabetes to early-stage DKD remain unclear. Free fatty acids, lactosylceramides and cardiolipin (CL) were identified as the most significantly altered lipids by quantitatively comparing targeted lipids in the renal cortex of the classic spontaneous diabetic db/db mice using high-coverage targeted lipidomics. Further investigation into the causes and effects of decreased CL, which is a unique mitochondrial phospholipid, was conducted in mitochondria-rich renal proximal tubular cells by using western blotting, real-time PCR, immunohistochemistry and transmission electron microscopy. Reduced expression of cardiolipin synthase, a key enzyme in the CL synthesis pathway, and inhibition of CL-related mitophagy were confirmed under high glucose conditions. In addition, the protective effect of CL-targeted Szeto-Schiller 31 in preserving mitophagy was demonstrated in both in vivo and in vitro studies. These findings provide new insights into the pathogenesis of early-stage DKD from a lipid perspective and offer a theoretical basis for discovering new treatments.