DsbA-L interacting with catalase in peroxisome improves tubular oxidative damage in diabetic nephropathy
Yan Liu,
Wei Chen,
Chenrui Li,
Li Li,
Ming Yang,
Na Jiang,
Shilu Luo,
Yiyun Xi,
Chongbin Liu,
Yachun Han,
Hao Zhao,
Xuejing Zhu,
Shuguang Yuan,
Li Xiao,
Lin Sun
Affiliations
Yan Liu
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Wei Chen
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Chenrui Li
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Li Li
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Ming Yang
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Na Jiang
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Shilu Luo
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Yiyun Xi
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Chongbin Liu
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Yachun Han
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Hao Zhao
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Xuejing Zhu
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Shuguang Yuan
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Li Xiao
Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Lin Sun
Corresponding author. Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China.; Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
Peroxisomes are metabolically active organelles that are known for exerting oxidative metabolism, but the precise mechanism remains unclear in diabetic nephropathy (DN). Here, we used proteomics to uncover a correlation between the antioxidant protein disulfide-bond A oxidoreductase-like protein (DsbA-L) and peroxisomal function. In vivo, renal tubular injury, oxidative stress, and cell apoptosis in high-fat diet plus streptozotocin (STZ)-induced diabetic mice were significantly increased, and these changes were accompanied by a ''ghost'' peroxisomal phenotype, which was further aggravated in DsbA-L-deficient diabetic mice. In vitro, the overexpression of DsbA-L in peroxisomes could improve peroxisomal phenotype and function, reduce oxidative stress and cell apoptosis induced by high glucose (HG, 30 mM) and palmitic acid (PA, 250 μM), but this effect was reversed by 3-Amino-1,2,4-triazole (3-AT, a catalase inhibitor). Mechanistically, DsbA-L regulated the activity of catalase by binding to it, thereby reducing peroxisomal leakage and proteasomal degradation of peroxisomal matrix proteins induced by HG and PA. Additionally, the expression of DsbA-L in renal tubules of patients with DN significantly decreased and was positively correlated with peroxisomal function. Taken together, these results highlight an important role of DsbA-L in ameliorating tubular injury in DN by improving peroxisomal function.
