한빛사 논문
DAE-YEON LEE#, JI-YEON KIM#, EUNYONG AHN#, JIN SEONG HYEON, GYU-HEE KIM, KEON-JAE PARK, YOUNGAE JUNG, YOO-JEONG LEE, MI KYOUNG SON, SEUNG WOO KIM, SANG YOUB HAN, JAE-HONG KIM, GU SEOB ROH, DAE RYONG CHA*, GEUM-SOOK HWANG*, and WON-HO KIM*
From the Division of Cardiovascular Disease Research, Korea National Institute of Health, Cheongju, Republic of Korea; Department of Anatomy and Convergence Medical Science, Bio Anti-aging Medical Research Center, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea; Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea; Division of Metabolic Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Republic of Korea; DepartDepartment of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Republic of Korea; Division of Life Sciences, College of Life Sciences, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea.
#These authors contributed equally to this work.
*Corresponding author.
Abstract
During the progression of diabetic kidney disease (DKD), renal lactate metabolism is rewired. The relationship between alterations in renal lactate metabolism and renal fibrosis in patients with diabetes has only been partially established due to a lack of biopsy tissues from patients with DKD and the intricate mechanism of lactate homeostasis. The role of lactate dehydrogenase A (LDHA)-mediated lactate generation in renal fibrosis and dysfunction in human and animal models of DKD was explored in this study. Measures of lactate metabolism (urinary lactate levels and LDHA expression) and measures of DKD progression (estimated glomerular filtration rate and Wilms’ tumor-1 expression) were strongly negatively correlated in patients with DKD. Experiments with streptozotocin-induced DKD rat models and the rat renal mesangial cell model confirmed our findings. We found that the pathogenesis of DKD is linked to hypoxia-mediated lactic acidosis, which leads to fibrosis and mitochondrial abnormalities. The pathogenic characteristics of DKD were significantly reduced when aerobic glycolysis or LDHA expression was inhibited. Further studies will aim to investigate whether local acidosis caused by renal LDHA might be exploited as a therapeutic target in patients with DKD.
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