Mitochondrial carnitine palmitoyltransferase 2 is involved in Nε-(carboxymethyl)-lysine-mediated diabetic nephropathy

• Published in: Pharmacological research 2020-02, Vol.152, p.104600, Article 104600
• Main Authors: Lee, Jangho, Hyon, Ju-Yong, Min, Jin Young, Huh, Yang Hoon, Kim, Hyo Jung, Lee, Hayoung, Yun, Sung Ho, Choi, Chi-Won, Jeong Ha, Su, Park, Joon, Chung, Young-Ho, Jeong, Hye Gwang, Ha, Sang Keun, Jung, Sung Keun, Kim, YoonSook, Han, Eun Hee
• Format: Article
• Language: English
• Subjects: Advanced glycation end products; Animals; Blood Glucose - analysis; Carnitine O-Palmitoyltransferase - genetics; Carnitine palmitoyltransferase 2; Cell Line; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 1 - chemically induced; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Diabetic Nephropathies - chemically induced; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic nephropathy (DN); End-stage renal disease; Glycated Hemoglobin A - analysis; Humans; Kidney - metabolism; Kidney - pathology; Lysine - analogs & derivatives; Male; Membrane Potential, Mitochondrial; Mice, Inbred C57BL; Mitochondria - enzymology; Mitochondria - physiology; Mitochondrial dysfunction; Nε-(carboxymethyl)-lysine
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2019.104600

Mechanisms of CML-induced DN via CPT2 downregulation. [Display omitted] •CML reduces CPT-2 production in streptozotocin-induced diabetic mice kidney.•CPT2 is associated with fatty acid oxidation and mitochondrial dysfunction.•CML-induced CPT2 down regulation causes mitochondrial FAO damage, leading to renal fibrosis and diabetic nephropathy. Diabetic nephropathy (DN) is the most common cause of end-stage renal disease in the world. Advanced glycation end products (AGEs) are thought to be involved in the pathogenesis of DN via multifactorial mechanisms including the generation of oxidative stress and overproduction of various growth factors and cytokines. AGEs are heterogeneous cross-linked sugar-derived proteins, and Nε-(carboxymethyl)-lysine (CML)-conjugated BSA is a major component of AGEs. However, the proteins involved in DN induction by CML have never been reported. Herein, we investigated specific protein regulators of AGE-mediated DN via proteomic analysis of streptozotocin (STZ)-induced diabetic mice kidneys. We identified 937, 976, and 870 proteins in control, STZ, and STZ + CML-BSA samples, respectively. Bioinformatics analysis identified several CML-mediated proteins potentially involved in kidney damage, activation of fatty acid oxidation (FAO), and mitochondrial dysfunction. Furthermore, we identified the CML-specific differential protein carnitine palmitoyltransferase 2 (CPT2), related to FAO. To confirm the effect of CPT2 and the CML-mediated mechanism, human renal tubular HK-2 cells were treated with CML-BSA and cpt2 siRNA, and examined for FAO-mediated fibrosis and mitochondrial dysfunction. CML-BSA and CPT2 knockdown induced fibrosis-related gene expression and damage to mitochondrial membrane potential. Moreover, CPT2 overexpression recovered CML-induced fibrosis-related gene expression. Based on these results, a decrease in CML-induced CPT2 expression causes mitochondrial FAO damage, leading to renal fibrosis and DN.