Upregulation of TIPE1 in tubular epithelial cell aggravates diabetic nephropathy by disrupting PHB2 mediated mitophagy
Lei Liu,
Fang Bai,
Hui Song,
Rong Xiao,
Yuzhen Wang,
Huimin Yang,
Xiaolei Ren,
Shuangjie Li,
Lifen Gao,
Chunhong Ma,
Xiangdong Yang,
Xiaohong Liang
Affiliations
Lei Liu
Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China; Department of Nephropathy, Qilu Hospital of Shandong University, Cheeloo Medical College, Shandong University, Jinan, Shandong, Jinan, Shandong, PR China
Fang Bai
Department of Nephropathy, Qilu Hospital of Shandong University, Cheeloo Medical College, Shandong University, Jinan, Shandong, Jinan, Shandong, PR China
Hui Song
Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China
Rong Xiao
Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China
Yuzhen Wang
Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China
Huimin Yang
Department of Nephropathy, Qilu Hospital of Shandong University, Cheeloo Medical College, Shandong University, Jinan, Shandong, Jinan, Shandong, PR China
Xiaolei Ren
Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China
Shuangjie Li
Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China
Lifen Gao
Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China; Shandong Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy, Jinan, Shandong, China
Chunhong Ma
Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China; Shandong Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy, Jinan, Shandong, China
Xiangdong Yang
Department of Nephropathy, Qilu Hospital of Shandong University, Cheeloo Medical College, Shandong University, Jinan, Shandong, Jinan, Shandong, PR China; Corresponding author. Department of Nephropathy, Qilu Hospital of Shandong University; Cheeloo Medical College, Shandong University, Jinan, 250000, China.
Xiaohong Liang
Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China; Shandong Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy, Jinan, Shandong, China; Corresponding author. Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology; School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, 250012, China.
Renal tubular epithelial cells (RTECs) are one of the most mitochondria-rich cell types, and are thus vulnerable to mitochondrial dysregulation, which is defined as a pivotal event in tubular damage in diabetic nephropathy (DN). However, the underlying mechanisms remain largely unknown. Here, we investigated the role and mechanisms of tumor necrosis factor alpha-induced protein 8-like 1 (TNFAIP8L1/TIPE1) in high glucose (HG)-induced mitochondrial dysfunction in RTECs and DN progression. TIPE1 expression was predominantly upregulated in RTECs in patients with DN and mice with streptozotocin (STZ)-induced DN. Conditional knockout of Tipe1 in RTECs significantly decreased the urine protein creatinine ratio, renal tubular damage, epithelial-mesenchymal transition, and interstitial fibrosis in STZ-induced mice. RNA sequencing revealed that citrate cycle-related genes were positively enriched in the renal tissues of RTEC-specific Tipe1 knockout mice. Tipe1 deficiency upregulated ATP levels, mitochondrial membrane potential, and respiration rate, but downregulated mitochondrial ROS levels in RTECs. Furthermore, Tipe1 ablation led to enhanced mitophagy in RTECs, indicative of increased LC3II, PINK1, and Parkin expression, but decreased p62 expression in mitochondria. Mechanistically, mass spectrometry screening and co-immunoprecipitation assays revealed the interaction of TIPE1 with prohibitin 2 (PHB2), a crucial mitophagy receptor. Intriguingly, TIPE1 promoted the ubiquitination and proteasomal degradation of PHB2. Subsequently, PHB2 knockdown almost abrogated the improvement of Tipe1 loss on HG-induced tubular cell mitophagy and damage. Thus, TIPE1 disrupts mitochondrial homeostasis in RTECs and promotes tubular damage by destabilizing PHB2 under HG conditions. Hence, TIPE1 may act as a potential therapeutic target to prevent DN progression.
