한빛사논문
순천향대학교
Jeong Suk Kang a,b, Nam-Jun Cho a,c, Seong Woo Lee a,d, Jeong Geon Lee c, Ji-Hye Lee c,e, Jawoon Yi f, Min Sun Choi a,d, Samel Park a,c, Hyo-Wook Gil a,c, Joon Cheol Oh c, Seung Seob Son a,d, Mi Ju Park a,d, Jong-Seok Moon g, Donghyeong Lee a,d, So-Young Kim a, Seung-Hoon Yang h, Sang Soo Kim i, Eun Soo Lee j,k, Choon Hee Chung j,k, Jihwan Parkf f, Eun Young Lee a,b,c,d
aDepartment of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
bInstitute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
cDepartment of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
dBK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
eDepartment of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
fSchool of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
gDepartment of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, Republic of Korea
hDepartment of Medical Biotechnology, College of Life Science and Biotechnology, Dongguk University, Seoul, Republic of Korea
iDepartment of Internal Medicine, Pusan National University Hospital, Busan, Republic of Korea
jDepartment of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
kResearch Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
Corresponding author: Eun Young Lee
Abstract
Background: Receptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 to podocyte injury in albuminuric diabetic kidney disease (DKD) remain unclear. Here, we investigated the role of RIPK3 in glomerular injury of DKD.
Methods: We analyzed RIPK3 expression levels in the kidneys of patients with biopsy-proven DKD and animal models of DKD. Additionally, to confirm the clinical significance of circulating RIPK3, RIPK3 was measured by ELISA in plasma obtained from a prospective observational cohort of patients with type 2 diabetes, and estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), which are indicators of renal function, were followed up during the observation period. To investigate the role of RIPK3 in glomerular damage in DKD, we induced a DKD model using a high-fat diet in Ripk3 knockout and wild-type mice. To assess whether mitochondrial dysfunction and albuminuria in DKD take a Ripk3-dependent pathway, we used single-cell RNA sequencing of kidney cortex and immortalized podocytes treated with high glucose or overexpressing RIPK3.
Results: RIPK3 expression was increased in podocytes of diabetic glomeruli with increased albuminuria and decreased podocyte numbers. Plasma RIPK3 levels were significantly elevated in albuminuric diabetic patients than in non-diabetic controls (p = 0.002) and non-albuminuric diabetic patients (p = 0.046). The participants in the highest tertile of plasma RIPK3 had a higher incidence of renal progression (hazard ratio [HR] 2.29 [1.05-4.98]) and incident chronic kidney disease (HR 4.08 [1.10-15.13]). Ripk3 knockout improved albuminuria, podocyte loss, and renal ultrastructure in DKD mice. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondrial ROS were decreased in podocytes of Ripk3 knockout DKD mice. In cultured podocytes, RIPK3 inhibition attenuated mitochondrial fission and mitochondrial dysfunction by decreasing p-mixed lineage kinase domain-like protein (MLKL), PGAM5, and p-Drp1 S616 and mitochondrial translocation of Drp1.
Conclusions: The study demonstrates that RIPK3 reflects deterioration of renal function of DKD. In addition, RIPK3 induces diabetic podocytopathy by regulating mitochondrial fission via PGAM5-Drp1 signaling through MLKL. Inhibition of RIPK3 might be a promising therapeutic option for treating DKD.
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