Loss of Functional SCO2 Attenuates Oxidative Stress in Diabetic Kidney Disease

Increased oxidative stress in glomerular endothelial cells (GEnCs) contributes to early diabetic kidney disease (DKD). While mitochondrial respiratory complex IV activity is reduced in DKD, it remains unclear whether this is a driver or a consequence of oxidative stress in GEnCs. Synthesis of cytochrome C oxidase 2 (SCO2), a key metallochaperone in the electron transport chain, is critical to the biogenesis and assembly of subunits required for functional respiratory complex IV activity. Here, we investigated the effects of Sco2 hypomorphs (Sco2KO/KI, Sco2KI/KI), with a functional loss of SCO2, in the progression of DKD using a murine model of Type II Diabetes Mellitus, db/db mice. Diabetic Sco2KO/KI and Sco2KI/KI hypomorphs exhibited a reduction in complex IV activity, but an improvement in albuminuria, serum creatinine, and histomorphometric evidence of early DKD as compared to db/db mice. Single-nucleus RNA sequencing with gene set enrichment analysis of differentially expressed genes in the endothelial cluster of Sco2KO/KI;db/db mice demonstrated an increase in genes involved in VEGF-VEGFR2 signaling and reduced oxidative stress as compared to db/db mice. These data suggest that reduced complex IV activity due to a loss of functional SCO2 might be protective in GEnCs in early DKD.

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CFAP45 is a Potential Predictor of Mitochondrial Dysfunction in Diabetic Kidney Disease

10.21203/rs.3.rs-277502/v1 ◽

2021 ◽

Author(s):

Yang Chen ◽

Min Shen ◽

Yun Shi ◽

Li Ji ◽

Yong Gu ◽

...

Keyword(s):

Kidney Disease ◽

Signaling Pathways ◽

Diabetic Kidney Disease ◽

Tricarboxylic Acid Cycle ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Diabetic Kidney ◽

Expression Levels ◽

Potential Biomarker

Abstract Background: Cilia and Flagella Associated Protein 45 (CFAP45) is known to be involved in the regulation of ciliary motility. However, its potential role in diabetic kidney disease (DKD) remains unknown. This study demonstrated the role of CFAP45 in the development of DKD based on the Gene Expression Omnibus database.Methods: First, we investigated the expression of CFAP45 in a whole-genome expression microarray (GSE30122). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, as well as Gene Set Enrichment Analysis (GSEA), were then conducted to identify the key signaling pathways associated with CFAP45. The networks between transcript factors and hub genes were then constructed by Cytoscape software.Findings: The expression levels of CFAP45 mRNA were reduced in DKD samples as compared to normal samples. Receiver operating characteristic (ROC) curve analysis suggested the significant discriminatory power (area under curve [AUC] = 0.811) of CFAP45 between DKD and normal tissues. Low expression levels of CFAP45 were correlated with apoptosis, senescence and the induction of mast cell infiltration. Function enrichment analysis indicated that CFAP45 is involved in the most significant hallmarks of mitochondrial metabolism dysfunction, including glycolysis and gluconeogenesis, fatty acid metabolism and degradation, ubiquitin-dependent protein catabolic processes, the tricarboxylic acid cycle (TCA) cycle, the action of oxidoreductase on Nicotinamide adenine dinucleotide (NADH), and the peroxisome proliferator-activated receptor (PPAR) signaling pathways located in the mitochondrial matrix and the lysosomal membrane. The transcription factor SMAD4 was found to negatively regulate the PPAR γ coactivator 1α (PGC1α). Interpretation: CFAP45 may regulate mitochondrial metabolic activity by affecting the function of the primary cilium on the kidney epithelial cells. CFAP45 may serve as a potential biomarker for the diagnosis and treatment of DKD.

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Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease

Antioxidants ◽

10.3390/antiox10071143 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1143

Author(s):

Midori Sakashita ◽

Tetsuhiro Tanaka ◽

Reiko Inagi

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Stress Responses ◽

Diabetic Kidney Disease ◽

Renin Angiotensin System ◽

Therapeutic Agents ◽

Metabolic Changes ◽

Diabetic Kidney ◽

Glucose Levels ◽

Patients With Diabetes

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease, and it is crucial to understand the pathophysiology of DKD. The control of blood glucose levels by various glucose-lowering drugs, the common use of inhibitors of the renin–angiotensin system, and the aging of patients with diabetes can alter the disease course of DKD. Moreover, metabolic changes and associated atherosclerosis play a major role in the etiology of DKD. The pathophysiology of DKD is largely attributed to the disruption of various cellular stress responses due to metabolic changes, especially an increase in oxidative stress. Therefore, many antioxidants have been studied as therapeutic agents. Recently, it has been found that NRF2, a master regulator of oxidative stress, plays a major role in the pathogenesis of DKD and bardoxolone methyl, an activator of NRF2, has attracted attention as a drug that increases the estimated glomerular filtration rate in patients with DKD. This review outlines the altered stress responses of cellular organelles in DKD, their involvement in the pathogenesis of DKD, and discusses strategies for developing therapeutic agents, especially bardoxolone methyl.

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N6 -(2-hydroxyethyl)-adenosine from Cordyceps cicadae protects against diabetic kidney disease via alleviation of oxidative stress and inflammation

Journal of Food Biochemistry ◽

10.1111/jfbc.12727 ◽

2018 ◽

Vol 43 (2) ◽

pp. e12727 ◽

Cited By ~ 6

Author(s):

Xiaohong Wang ◽

Aiqiong Qin ◽

Fang Xiao ◽

Opeyemi J. Olatunji ◽

Shuyuan Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Cordyceps Cicadae

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Sulodexide Protects Renal Tubular Epithelial Cells from Oxidative Stress-Induced Injury via Upregulating Klotho Expression at an Early Stage of Diabetic Kidney Disease

Journal of Diabetes Research ◽

10.1155/2017/4989847 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Yu Ning Liu ◽

Jingwei Zhou ◽

Tingting Li ◽

Jing Wu ◽

Shu Hua Xie ◽

...

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Epithelial Cells ◽

Diabetic Kidney Disease ◽

Early Stage ◽

Collaborative Study ◽

Oxidative Activity ◽

Dependent Manner ◽

Diabetic Kidney ◽

Collaborative Study Group

The hypoalbuminuric effect of sulodexide (SDX) on diabetic kidney disease (DKD) was suggested by some clinical trials but was denied by the Collaborative Study Group. In this study, the diabetic rats were treated with SDX either from week 0 to 24 or from week 13 to 24. We found that 24-week treatment significantly decreased the urinary protein and HAVCR1 excretion, inhibited the interstitial expansion, and downregulated the renal cell apoptosis and interstitial fibrosis. Renoprotection was also associated with a reduction in renocortical/urinary oxidative activity and the normalization of renal klotho expression. However, all of these actions were not observed when SDX was administered only at the late stage of diabetic nephropathy (from week 13 to 24). In vitro, advanced glycation end products (AGEs) dose-dependently enhanced the oxidative activity but lowered the klotho expression in cultured proximal tubule epithelial cells (PTECs). Also, H2O2 could downregulate the expression of klotho in a dose-dependent manner. However, overexpression of klotho reduced the HAVCR1 production and the cellular apoptosis level induced by AGEs or H2O2. Our study suggests that SDX may prevent the progression of DKD at the early stage by upregulating renal klotho expression, which inhibits the tubulointerstitial injury induced by oxidative stress.

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Loss of Functional SCO2 Attenuates Oxidative Stress in Diabetic Kidney Disease

Diabetes ◽

10.2337/db21-0316 ◽

2021 ◽

pp. db210316

Author(s):

Nehaben A. Gujarati ◽

Alexandra R. Leonardo ◽

Jessica M. Vasquez ◽

Yiqing Guo ◽

Bismark O. Frimpong ◽

...

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Diabetic Kidney

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Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

International Journal of Molecular Sciences ◽

10.3390/ijms221910822 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10822

Author(s):

Agata Winiarska ◽

Monika Knysak ◽

Katarzyna Nabrdalik ◽

Janusz Gumprecht ◽

Tomasz Stompór

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Kidney Injury ◽

Organ Protection ◽

In Vivo Models ◽

Diabetic Kidney ◽

And Oxidative Stress

The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) antagonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress—the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R antagonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.

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