Advanced oxidation protein products contribute to renal tubulopathy via perturbation of renal fatty acids

Background: Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Since proximal tubular cells consume much energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracted attention. The purpose of this study is to investigate the association between change in renal fatty acids (FAs) composition and tubulopathy. Methods: Mice with cisplatin-induced nephrotoxicity was used as AKI model and 5/6-nephrectomized mice was used as CKD model. Renal FAs composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) was used for in vitro study. Results: In kidneys of AKI mice, increased stearate (C18:0) and decreased palmitate (C16:0) were observed, accompanied by increasing expression of the long-chain FAs elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, it is demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6-knock out suppressed the increased serum creatinine level, renal ER stress and inflammation as observed after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was identified as inducing Elovl6 via the mTORC1/SREBP1 pathway. Conclusions: AOPPs may contribute to renal tubulopathy via perturbation of renal FAs through Elovl6 induction. The perturbation of renal fatty acids induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.