scholarly journals miR-23a-3p regulates the inflammatory response and fibrosis in diabetic kidney disease by targeting early growth response 1

2021 ◽  
Author(s):  
Shuyue Sheng ◽  
Meina Zou ◽  
Yanlin Yang ◽  
Meiping Guan ◽  
Shijing Ren ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Growth Response ◽  
Diabetic Kidney Disease ◽  
Early Growth ◽  
Diabetic Kidney ◽  
Expression Levels ◽  
Early Growth Response ◽  
Tnf Α ◽  
Renal Tubular ◽  
Early Growth Response 1

AbstractDiabetic kidney disease (DKD) has become the most common cause of chronic kidney disease. Proteinuria is generally considered one of the clinical indicators of renal damage, and it is also closely related to the progression of DKD. Accumulating evidence indicates that proteinuria induces an upregulation of the expression levels of inflammatory cytokines and fibrosis markers in renal tubular epithelial cells, but the mechanism remains unclear. Previously, we showed that early growth response 1 (Egr1) played a key role in renal tubular injury. However, the upstream mechanism of Egr1 in the development of DKD is poorly understood. In this study, we found that albumin stimulation significantly increased the expression levels of Egr1, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and fibronectin (FN) in HK-2 cells but decreased miR-23a-3p levels. We then identified that miR-23a-3p targeted the 3′ untranslated region (UTR) of Egr1 and directly suppressed the expression of Egr1. Moreover, we found that overexpression and inhibition of miR-23a-3p in HK-2 cells attenuated and promoted the expression of IL-6, TNF-α, and FN, respectively. Additionally, Egr1 silencing reversed the inflammation and fibrosis caused by the miR-23a-3p inhibitor. Thus, we conclude that miR-23a-3p attenuates the development of DKD through Egr1, suggesting that targeting miR-23a-3p may be a novel therapeutic approach for DKD.

scholarly journals Lipoxins Regulate the Early Growth Response–1 Network and Reverse Diabetic Kidney Disease

2018 ◽  
Vol 29 (5) ◽  
pp. 1437-1448 ◽  
Author(s):  
Eoin P. Brennan ◽  
Muthukumar Mohan ◽  
Aaron McClelland ◽  
Christos Tikellis ◽  
Mark Ziemann ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Growth Response ◽  
Diabetic Kidney Disease ◽  
Microvascular Complications ◽  
Disease Onset ◽  
Early Growth ◽  
Resolution Of Inflammation ◽  
Diabetic Kidney ◽  
Early Growth Response ◽  
Early Growth Response 1

Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation.Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE−/− mice treated with streptozotocin.Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10 weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renal proinflammatory/profibrotic signals (TNF-α, IL-1β, NF-κB). In diabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (early growth response–1 [EGR-1]) networks activated in diabetes and regulated by LXs. In cultured human renal epithelial cells, treatment with LXs attenuated TNF-α–driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α.Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.

scholarly journals Early Growth Response 1 (Egr1) Is a Transcriptional Activator of NOX4 in Oxidative Stress of Diabetic Kidney Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Fang Hu ◽  
Meng Xue ◽  
Yang Li ◽  
Yi-Jie Jia ◽  
Zong-Ji Zheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Transcriptional Activator ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Early Growth Response ◽  
Nadph Oxidase 4 ◽  
Early Growth Response 1 ◽  
The Relationship

Background. NADPH oxidase 4 (NOX4) plays a major role in renal oxidative stress of diabetic kidney disease (DKD). NOX4 was significantly increased in Egr1-expressing fibroblasts, but the relationship between Egr1 and NOX4 in DKD is unclear. Methods. For the evaluation of the potential relationship between Egr1 and NOX4, both were detected in HFD/STZ-induced mice and HK-2 cells treated with TGF-β1. Then, changes in NOX4 expression were detected in HK-2 cells and mice with overexpression and knockdown of Egr1. The direct relationship between Egr1 and NOX4 was explored via chromatin immunoprecipitation (ChIP). Results. We found increased levels of Egr1, NOX4, and α-SMA in the kidney cortices of diabetic mice and in TGF-β1-treated HK-2 cells. Overexpression or silencing of Egr1 in HK-2 cells could upregulate or downregulate NOX4 and α-SMA. ChIP assays revealed that TGF-β1 induced Egr1 to bind to the NOX4 promoter. Finally, Egr1 overexpression or knockdown in diabetic mice could upregulate or downregulate the expression of NOX4 and ROS, and α-SMA was also changed. Conclusion. Our study provides strong evidence that Egr1 is a transcriptional activator of NOX4 in oxidative stress of DKD. Egr1 contributes to DKD by enhancing EMT, in part by targeting NOX4.

scholarly journals Early growth response protein-1 upregulates long noncoding RNA Arid2-IR to promote extracellular matrix production in diabetic kidney disease

2019 ◽  
Vol 316 (3) ◽  
pp. C340-C352 ◽  
Author(s):  
Yan-Lin Yang ◽  
Fang Hu ◽  
Meng Xue ◽  
Yi-Jie Jia ◽  
Zong-Ji Zheng ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Kidney Disease ◽  
High Glucose ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Growth Response ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Early Growth ◽  
Early Growth Response

Diabetic kidney disease (DKD) has surpassed chronic glomerulonephritis as the leading cause of end-stage renal disease. Previously, we showed that early growth response protein-1 (Egr1) plays a key role in DKD by enhancing mesangial cell proliferation and extracellular matrix (ECM) production. The long noncoding RNA (lncRNA) AT-rich interactive domain 2-IR (Arid2-IR) has been identified as a mothers against decapentaplegic homolog 3 (Smad3)-associated lncRNA in unilateral ureteral obstructive kidney disease. However, the effect of Egr1 on Arid2-IR in the development of DKD is still unknown. In this study, we found that Arid2-IR was increased in mice with high-fat diet and streptozotocin-induced type 2 diabetes and in mouse mesangial cells cultured with high glucose to mimic diabetes. Knockdown of Arid2-IR in mouse mesangial cells reduced the high expression levels of collagen-α1(I) (Col1a1) and α-smooth muscle actin (α-SMA) induced by high glucose. Furthermore, Arid2-IR expression changed the increased expression of Col1a1 and α-SMA caused by overexpression of Egr1. Overall, these data suggest that increased Arid2-IR likely contributes to ECM production in DKD and that Egr1 promotes ECM production in DKD partly by upregulating Arid2-IR. Thus, Arid2-IR may be a new target in the treatment of DKD.

Social isolation stress down-regulates cortical early growth response 1 (Egr-1) expression in mice

2012 ◽  
Vol 73 (3) ◽  
pp. 257-262 ◽  
Author(s):  
Kinzo Matsumoto ◽  
Kazuya Ono ◽  
Hirofumi Ouchi ◽  
Ryohei Tsushima ◽  
Yukihisa Murakami
Keyword(s):  
Social Isolation ◽  
Growth Response ◽  
Early Growth ◽  
Isolation Stress ◽  
Early Growth Response ◽  
Social Isolation Stress ◽  
Early Growth Response 1
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