Beneficial Effect of Chloroquine and Amodiaquine on Type 1 Diabetic Tubulopathy by Attenuating Mitochondrial Nox4 and Endoplasmic Reticulum Stress

Kang, Jun Mo; Lee, Hyun‐Seob; Kim, Jung-Hyun; Yang, Dong Ho; Jeong, Hye Yun; Lee, Yu Ho; Kim, Dong Jin; Park, Seon Hwa; Sung, Min-Ji; Kim, Jaehee; An, Hyun Ju; Lee, Sang Ho; Lee, So Young

doi:10.3346/jkms.2020.35.e305

Cited by 13 publications

(9 citation statements)

References 41 publications

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“…Estrogens and androgens are known to serve as protectors of osteoblasts by reducing oxidative stress in the extracellular-signal-regulated kinase (ERK)-dependent manner [ 59 , 60 ]. ROS occurs primarily in the mitochondria due to the escape of electrons through the OXPHOS, which is responsible for the production of ATPs [ 61 ]. In our study, post Pink1 siRNA treatment, there was an increase in the production of ROS in osteoblasts, indicating that mitochondrial quality control by PINK1 is a protective method against excess mitochondrial ROS development that allows further osteoblastogenesis to proceed normally.…”

Section: Discussionmentioning

confidence: 99%

PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis

Lee

Kim

et al. 2021

Stem Cell Res Ther

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Background PTEN-induced kinase 1 (PINK1) is a serine/threonine-protein kinase in mitochondria that is critical for mitochondrial quality control. PINK1 triggers mitophagy, a selective autophagy of mitochondria, and is involved in mitochondrial regeneration. Although increments of mitochondrial biogenesis and activity are known to be crucial during differentiation, data regarding the specific role of PINK1 in osteogenic maturation and bone remodeling are limited. Methods We adopted an ovariectomy model in female wildtype and Pink1−/− mice. Ovariectomized mice were analyzed using micro-CT, H&E staining, Masson’s trichrome staining. RT-PCR, western blot, immunofluorescence, alkaline phosphatase, and alizarin red staining were performed to assess the expression of PINK1 and osteogenic markers in silencing of PINK1 MC3T3-E1 cells. Clinical relevance of PINK1 expression levels was determined via qRT-PCR analysis in normal and osteoporosis patients. Results A significant decrease in bone mass and collagen deposition was observed in the femurs of Pink1−/− mice after ovariectomy. Ex vivo, differentiation of osteoblasts was inhibited upon Pink1 downregulation, accompanied by impaired mitochondrial homeostasis, increased mitochondrial reactive oxygen species production, and defects in mitochondrial calcium handling. Furthermore, PINK1 expression was reduced in bones from patients with osteoporosis, which supports the practical role of PINK1 in human bone disease. Conclusions In this study, we demonstrated that activation of PINK1 is a requisite in osteoblasts during differentiation, which is related to mitochondrial quality control and low reactive oxygen species production. Enhancing PINK1 activity might be a possible treatment target in bone diseases as it can promote a healthy pool of functional mitochondria in osteoblasts.

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Section: Discussionmentioning

confidence: 99%

PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis

Lee

Kim

et al. 2021

Stem Cell Res Ther

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“…An accumulating body of evidence, from both clinical scenarios and experimental animal models, supports the fact that hyperglycemia induces apoptosis through ER stress in tubular cells, at least in part, and that this process contributes to the pathogenesis of DT ( Kang et al, 2020 ). ER stress generally occurs under normal physiological and pathological conditions and represents an important inducer of cell apoptosis ( Cybulsky, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…Several reports show the effects of thiazolidinediones (TZDs) including ROS on ER stress. It is well known that ER stress is involved in the development of insulin resistance and type 2 diabetes mellitus, and TZDs are antidiabetic agents that act as a potent insulin sensitizer ( Kang et al, 2013 ; Kang et al, 2020 ). Thus, targeting ER stress in diabetic kidneys, ROS was chosen as a positive control in this study.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Renal Tubular Epithelial Mesenchymal Transition and Endoplasmic Reticulum Stress-Induced Apoptosis with Shenkang Injection Attenuates Diabetic Tubulopathy

et al. 2021

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Background: The proximal renal tubule plays a critical role in diabetic kidney disease (DKD) progression. Early glomerular disease in DKD triggers a cascade of injuries resulting in renal tubulointerstitial disease. These pathophysiological responses are collectively described as diabetic tubulopathy (DT). Thus, therapeutic strategies targeting DT hold significant promise for early DKD treatment. Shenkang injection (SKI) has been widely used to treat renal tubulointerstitial fibrosis in patients with chronic kidney disease in China. However, it is still unknown whether SKI can alleviate DT. We designed a series of experiments to investigate the beneficial effects of SKI in DT and the mechanisms that are responsible for its effect on epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress-induced apoptosis in DT.Methods: The modified DKD rat models were induced by uni-nephrectomy, streptozotocin intraperitoneal injection, and a high-fat diet. Following the induction of renal injury, these animals received either SKI, rosiglitazone (ROS), or vehicle, for 42 days. For in vitro research, we exposed NRK-52E cells to high glucose (HG) and 4-phenylbutyric acid (4-PBA) with or without SKI or ROS. Changes in parameters related to renal tubular injury and EMT were analyzed in vivo. Changes in the proportion of apoptotic renal tubular cells and ER stress, and the signaling pathways involved in these changes, were analyzed both in vivo and in vitro.Results: SKI and ROS improved the general condition, the renal morphological appearance and the key biochemical parameters, and attenuated renal injury and EMT in the rat model of DKD. In addition, SKI and ROS alleviated apoptosis, inhibited ER stress, and suppressed PERK-eIF2α-ATF4-CHOP signaling pathway activation both in vivo and in vitro. Notably, our data showed that the regulatory in vitro effects of SKI on PERK-eIF2α-ATF4-CHOP signaling were similar to those of 4-PBA, a specific inhibitor of ER stress.Conclusion: This study confirmed that SKI can alleviate DT in a similar manner as ROS, and SKI achieves this effect by inhibiting EMT and ER stress-induced apoptosis. Our findings thereby provide novel information relating to the clinical value of SKI in the treatment of DT.

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“…Human renal proximal tubular epithelial cells (HK-2) (ATCC, USA) were cultured in DMEM/F12 (Invitrogen, Carlsbad, CA, USA) with 10% fetal bovine serum (FBS, Sciencell, USA) and 1% penicillin/streptomycin (PS, Beyotime, Shanghai, China) at 37°C and 5% CO2 [ 43 ]. MaR1 (100 μ M, Cayman Chemical, MI, USA) was added to high glucose (HG) for 72 h to investigate the effects on high glucose-induced HK-2 cells.…”

Section: Methodsmentioning

confidence: 99%

Maresin 1 Alleviates Diabetic Kidney Disease via LGR6-Mediated cAMP-SOD2-ROS Pathway

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Chronic hyperglycemia-induced inflammation is recognized as the most important pathophysiological process in diabetic kidney disease (DKD). As maresin 1 (MaR1) is an extensive anti-inflammatory lipid mediator, the present study investigated the protective role of MaR1 in the pathogenesis of DKD and its clinical relevance. Methods. Serum MaR1 concentrations were analyzed in 104 subjects with normal glucose tolerant, type 2 diabetes (T2DM), or DKD. Streptozotocin (STZ) together with high fat diet was used to induce male C57BL/6 J mice into diabetic mice which were treated with MaR1. Human renal tubule epithelial cells (HK-2 cells) were treated by high glucose for glucotoxicity cell model and transfected with LGR6 siRNA for knockdown with MaR1 added，and detected oxidative stress and inflammatory related factors. Results. Serum MaR1 concentrations were significant decreased in T2DM with or without kidney disease compared with normal participant and were lowest in patients with DKD. Serum MaR1 concentrations were negatively correlated with hemoglobin A1c (HbA1c), duration of diabetes, urinary albumin to creatinine ratio (UACR), neutrophil, and neutrophil-lymphocyte ratio and were positively correlated with high-density lipoprotein-cholesterol (HDL-C) and estimated glomerular filtration rate (eGFR). In mouse model, MaR1 injection alleviated hyperglycemia, UACR and the pathological progression of DKD. Interestingly, the renal expression of LGR6 was down-regulated in DKD and high glucose treated HK-2 cells but up-regulated by MaR1 treatment. Mechanistically, MaR1 alleviated inflammation via LGR6-mediated cAMP-SOD2 antioxidant pathway in DKD mice and high glucose treated HK-2 cells. Conclusions. Our study demonstrates that decreased serum MaR1 levels were correlated with the development of DKD. MaR1 could alleviate DKD and glucotoxicity-induced inflammation via LGR6-mediated cAMP-SOD2 antioxidant pathway. Thus, our present findings identify MaR1 as a predictor and a potential therapeutic target for DKD.

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Beneficial Effect of Chloroquine and Amodiaquine on Type 1 Diabetic Tubulopathy by Attenuating Mitochondrial Nox4 and Endoplasmic Reticulum Stress

Cited by 13 publications

References 41 publications

PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis

PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis

Inhibition of Renal Tubular Epithelial Mesenchymal Transition and Endoplasmic Reticulum Stress-Induced Apoptosis with Shenkang Injection Attenuates Diabetic Tubulopathy

Maresin 1 Alleviates Diabetic Kidney Disease via LGR6-Mediated cAMP-SOD2-ROS Pathway

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