Dyslipidemia-induced renal fibrosis related to ferroptosis and endoplasmic reticulum stress

• DOI: 10.1016/j.jlr.2024.100610
• Publication Date: 2024-07-31T22:20:28Z
• Authors: Yamei Jiang; Xiangyang Zhu; Kyra Jordan; Yongxin Li; Sabena Conley; Hui Tang; Amir Lerman; Alfonso Eirin; Tongwen Ou; Lilach O. Lerman
• Keywords: PCSK9; Dyslipidemia

Dyslipidemia may induce chronic kidney disease and trigger both ferroptosis endoplasmic reticulum (ER) stress, but the instigating factors are incompletely understood. We tested hypothesis that different models of dyslipidemia engage distinct injury mechanisms. Wild-type (WT) or proprotein-convertase subtilisin/kexin type-9 (PCSK9)-gain-of-function (GOF) Ossabaw pigs were fed with a 6-month normal diet (ND) high-fat (HFD) (n = 5-6 each). Renal function fat deposition studied in vivo using CT, blood tissue ex-vivo for lipid profile, systemic renal vein FFAs levels, mechanisms including peroxidation, ferroptosis, ER stress. Compared WT-ND pigs, HFD PCSK9-GOF elevated triglyceride which highest WT-HFD, whereas total LDL cholesterol levels rose only particularly PCSK9-GOF/HFD. The groups had worse than ND groups. WT-HFD kidneys retained more FFA other groups, all developed fibrosis. Furthermore, HFD-induced indicated by increased free iron, decreased glutathione peroxidase-4 mRNA expression, while induced stress upregulated GRP94 CHOP protein expression. In vitro, pig epithelial cells treated palmitic acid oxidized to mimic showed similar trends those observed vivo. Taken together, hypertriglyceridemia promotes retention PCSK9-GOF-induced hypercholesterolemia elicits resulting These observations suggest targets preventing treating fibrosis subjects specific types dyslipidemia.