cGAS-STING activation contributes to podocyte injury in diabetic kidney disease

Zang, Nan; Guo, Xinghong; Song, Jia; Hu, Huiqing; Xu, Mingyue; Wang, Lingshu; Hou, Xinguo; He, Qin; Sun, Zheng; Wang, Chuan; Chen, Li

doi:10.1016/j.isci.2022.105145

Cited by 49 publications

(37 citation statements)

References 42 publications

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“…The destruction of glomerular ltration membrane structure is the common mechanism of various glomerular diseases characterized by proteinuria. Podocytes, as an important component of glomerular ltration membrane, have obvious correlation with the occurrence and development of DKD [25,26]. In physiological state, podocytes have a high level of autophagic activity, which can achieve the needs of self-metabolism and the renewal of organelles.…”

Section: Discussionmentioning

confidence: 99%

DDIT4 mediated autophagy and ferroptosis through VDR-mTOR signaling pathway in the treatment of diabetic kidney disease

Jiao

et al. 2022

Preprint

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To determine the changes in the expression of DNA damage inducing transcription factor 4 (DDIT4) and the gene related to the activation of vitamin D receptor (VDR) in diabetic kidney disease (DKD) patients and experimental mice, and to explore the molecular mechanism of DDIT4 in the treatment of DKD. The pathological damage of kidney tissue and the molecular expression of VDR-mTOR related pathway in DKD patients and db/db mouse models were observed by periodate schiff (PAS) staining and immunohistochemistry (IHC) staining; furthermore, diabetic cell models were established in mouse immortalized kidney podocyte line MPC5 cells and mouse glomerular mesangial cell line SV40-MES-13 cells by high glucose culture, transfected with DDIT4 plasmid, observed cell morphological changes by transmission electron microscopy and laser confocal microscopy, and detected VDR/mTOR/p70s6k/4E-BP1 signal pathway protein expression by qRT-PCR and western blotting. PAS staining and IHC staining results showed that pathological damage of kidney tissue was observed in samples of DKD patients and in db/db mouse models. The results of qRT-PCR and western blotting showed that the expression of related proteins in VDR mTOR signal pathway changed. DDIT4 treatment could increase the expression of VDR, and reduce the expression of mTOR, p70s6k, 4E-BP1. The autophagy level showed that DDIT4 treatment could increase the expression of LC3I and decrease the expression of LC3II. The results of ferroptosis detection showed that DDIT4 treatment could reduce the expression of MDA and increase the expression of SOD and GSH. By participating in the VDR/mTOR/p70s6k/4E-BP1 signaling pathway, DDIT4 affects the process of autophagy and ferroptosis, thereby improving the pathological damage of diabetic kidney disease, and may become a new target for the treatment of DKD.

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Section: Discussionmentioning

confidence: 99%

DDIT4 mediated autophagy and ferroptosis through VDR-mTOR signaling pathway in the treatment of diabetic kidney disease

Jiao

et al. 2022

Preprint

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“…Studies have also demonstrated that STING contributes to the development of diabetic kidney disease [ 251 ]. Cytoplasmic leakage of mtDNA was sufficient to cause kidney inflammation via activation of the cGAS-STING signaling pathway [ 252 , 253 ]. Knockdown or pharmacological inhibition of STING can reduce podocyte injury and improve renal functions in mouse diabetic models [ 253 ].…”

Section: Sting-related Diseasesmentioning

confidence: 99%

“…Cytoplasmic leakage of mtDNA was sufficient to cause kidney inflammation via activation of the cGAS-STING signaling pathway [ 252 , 253 ]. Knockdown or pharmacological inhibition of STING can reduce podocyte injury and improve renal functions in mouse diabetic models [ 253 ]. In addition, Feng et al found that STING expression was upregulated at diabetic skin wound sites, where STING activation delayed wound healing [ 254 ], and silencing or inhibiting STING accelerated wound healing [ 254 ].…”

Section: Sting-related Diseasesmentioning

confidence: 99%

Potential Therapeutic Value of the STING Inhibitors

2023

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The stimulator of interferon genes (STING) is a critical protein in the activation of the immune system in response to DNA. It can participate the inflammatory response process by modulating the inflammation-preferred translation program through the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway or by inducing the secretion of type I interferons (IFNs) and a variety of proinflammatory factors through the recruitment of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) or the regulation of the nuclear factor kappa-B (NF-κB) pathway. Based on the structure, location, function, genotype, and regulatory mechanism of STING, this review summarizes the potential value of STING inhibitors in the prevention and treatment of infectious diseases, psoriasis, systemic lupus erythematosus, non-alcoholic fatty liver disease, and other inflammatory and autoimmune diseases.

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“…High levels of ROS were shown to induce mitochondrial permeability transition pore opening and increase Cyt C release, leading to mitochondrial dysfunction, organelle swelling, and cell apoptosis and death [13, 30]. Mitochondrial damage also leads to mtDNA leakage, which in turn overactivates the cyclic GMP-AMP synthase-stimulator of interferon genes pathway to cause podocyte injury [31]. Sustained high mtROS levels also damage macromolecules, such as DNA, proteins, and lipids.…”

Section: Mitochondrial Abnormalities In Fsgsmentioning

confidence: 99%

Therapeutic Potential Targeting Podocyte Mitochondrial Dysfunction in Focal Segmental Glomerulosclerosis

Li¹,

Fan²,

Zhu³

et al. 2023

Kidney Dis

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Background：Podocytes are essential components of the glomerular filtration barrier and essential for the proper filtration function of the glomerulus. Podocyte injury under various stress conditions is the primary pathogenesis and key determinant of focal segmental glomerulosclerosis (FSGS) with prominent clinical manifestations of proteinuria or nephrotic syndrome. Summary：Under physiological conditions, a highly coordinated mitochondrial quality control system, including antioxidant defenses, mitochondrial dynamics (fusion, fission and mitophagy), and mitochondrial biogenesis, guarantees the sophisticated structure and various functions of podocytes. However, under FSGS pathological conditions, mitochondria encounter oxidative stress, dynamics disturbances, and defective mitochondrial biogenesis. Moreover, mutations in mtDNA and mitochondria-related genes are also strongly associated with FSGS. Based on these evidences, bioactive agents that function to relieve mitochondrial oxidative stress and promote mitochondrial biogenesis have been proven effective in pre-clinical FSGS models. Targeting the mitochondrial network is expected to provide new therapeutic strategies for the treatment of FSGS and delay its progression to end-stage renal disease (ESRD). Key messages：Mitochondrial dysfunction plays a key role in podocyte injury and FSGS progression. This review summarized recent advances in the study of mitochondrial homeostatic imbalance and dysfunction in FSGS and discussed the potential of mitochondria-targeted therapeutics in improving FSGS and retarding its progression to ESRD.

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cGAS-STING activation contributes to podocyte injury in diabetic kidney disease

Cited by 49 publications

References 42 publications

DDIT4 mediated autophagy and ferroptosis through VDR-mTOR signaling pathway in the treatment of diabetic kidney disease

DDIT4 mediated autophagy and ferroptosis through VDR-mTOR signaling pathway in the treatment of diabetic kidney disease

Potential Therapeutic Value of the STING Inhibitors

Therapeutic Potential Targeting Podocyte Mitochondrial Dysfunction in Focal Segmental Glomerulosclerosis

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