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.

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 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 BKCa Mediates Dysfunction in High Glucose Induced Mesangial Cell Injury via TGF-β1/Smad2/3 Signaling Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Zhigui Wu ◽  
Wenxian Yin ◽  
Mengqi Sun ◽  
Yuankai Si ◽  
Xiaoxiao Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Diabetic Kidney

Objective. To explore the role and mechanism of BKCa in diabetic kidney disease. Methods. Rat mesangial cells (MCs) HBZY-1 were cultured with high glucose to simulate the high-glucose environment of diabetic kidney disease in vivo. The effects of large conductance calcium-activated potassium channel (BKCa) on proliferation, migration, and apoptosis of HBZY-1 cells were observed. The contents of transforming growth factor beta 1 (TGF-β1), Smad2/3, collagen IV (Col IV), and fibronectin (FN) in the extracellular matrix were also observed. Results. High glucose significantly damaged HBZY-1 cells, which enhanced the ability of cell proliferation, migration, and apoptosis, and increased the secretion of Col IV and FN. Inhibition of BKCa and TGF-β1/Smad2/3 signaling pathways can inhibit the proliferation, migration, and apoptosis of HBZY-1 cells and suppress the secretion of Col IV and FN. The effect of excitation is the opposite. Conclusions. BKCa regulates mesangial cell proliferation, migration, apoptosis, and secretion of Col IV and FN and is associated with TGF-β1/Smad2/3 signaling pathway.

Cell-extracellular matrix interactions can regulate the switch between growth and differentiation in rat hepatocytes: reciprocal expression of C/EBP alpha and immediate-early growth response transcription factors

1994 ◽  
Vol 14 (9) ◽  
pp. 5858-5869
Author(s):  
B Rana ◽  
D Mischoulon ◽  
Y Xie ◽  
N L Bucher ◽  
S R Farmer
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factors ◽  
Dna Binding ◽  
Growth Response ◽  
Isolated Hepatocytes ◽  
Early Growth ◽  
Binding Activity ◽  
Early Growth Response ◽  
Dna Binding Activity ◽  
Rat Tail

Previous investigations have shown that culture of freshly isolated hepatocytes under conventional conditions, i.e., on dried rat tail collagen in the presence of growth factors, facilitates cell growth but also causes an extensive down-regulation of most liver-specific functions. This dedifferentiation process can be prevented if the cells are cultured on a reconstituted basement membrane gel matrix derived from the Englebreth-Holm-Swarm mouse sarcoma tumor (EHS gel). To gain insight into the mechanisms regulating this response to extracellular matrix, we are analyzing the activities of two families of transcription factors, C/EBP and AP-1, which control the transcription of hepatic and growth-responsive genes, respectively. We demonstrate that isolation of hepatocytes from the normal quiescent rat liver by collagenase perfusion activates the immediate-early growth response program, as indicated by increased expression of c-jun, junB, c-fos, and c-myc mRNAs. Adhesion of these activated cells to dried rat tail collagen augments the elevated levels of these mRNAs for the initial 1 to 2 h postplating; junB and c-myc mRNA levels then drop steeply, with junB returning to normal quiescence and the c-myc level remaining slightly elevated during the 3-day culture period. Levels of c-jun mRNA and AP-1 DNA binding activity, however, remain elevated from the outset, while C/EBP alpha mRNA expression is down-regulated, resulting in a decrease in the steady-state levels of the 42- and 30-kDa C/EBP alpha polypeptides and C/EBP alpha DNA binding activity. In contrast, C/EBP beta mRNA production remains at near-normal hepatic levels for 5 to 8 days of culture, although its DNA binding activity decreases severalfold during this time. Adhesion of hepatocytes to the EHS gel for the same period of time dramatically alters this program: it arrests growth and inhibits AP-1 DNA binding activity and the expression of c-jun, junB, and c-myc mRNAs, but, in addition, it restores C/EBP alpha mRNA and protein as well as C/EBP alpha and C/EBP beta DNA binding activities to the abundant levels present in freshly isolated hepatocytes. These changes are not due merely to growth inhibition, because suppression of hepatocyte proliferation on collagen by epidermal growth factor starvation or addition of transforming growth factor beta does not inhibit AP-1 activity or restore C/EBP alpha DNA binding activity to normal hepatic levels. These data suggest that expression of the normal hepatic phenotype requires that hepatocytes exist in a G0 state of growth arrest, facilitated here by adhesion of cells to the EHS gel, in order to express high levels of hepatic transcription factors such as C/EBP alpha.

scholarly journals Cell-extracellular matrix interactions can regulate the switch between growth and differentiation in rat hepatocytes: reciprocal expression of C/EBP alpha and immediate-early growth response transcription factors.

1994 ◽  
Vol 14 (9) ◽  
pp. 5858-5869 ◽  
Author(s):  
B Rana ◽  
D Mischoulon ◽  
Y Xie ◽  
N L Bucher ◽  
S R Farmer
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factors ◽  
Dna Binding ◽  
Growth Response ◽  
Isolated Hepatocytes ◽  
Early Growth ◽  
Binding Activity ◽  
Early Growth Response ◽  
Dna Binding Activity ◽  
Rat Tail

Previous investigations have shown that culture of freshly isolated hepatocytes under conventional conditions, i.e., on dried rat tail collagen in the presence of growth factors, facilitates cell growth but also causes an extensive down-regulation of most liver-specific functions. This dedifferentiation process can be prevented if the cells are cultured on a reconstituted basement membrane gel matrix derived from the Englebreth-Holm-Swarm mouse sarcoma tumor (EHS gel). To gain insight into the mechanisms regulating this response to extracellular matrix, we are analyzing the activities of two families of transcription factors, C/EBP and AP-1, which control the transcription of hepatic and growth-responsive genes, respectively. We demonstrate that isolation of hepatocytes from the normal quiescent rat liver by collagenase perfusion activates the immediate-early growth response program, as indicated by increased expression of c-jun, junB, c-fos, and c-myc mRNAs. Adhesion of these activated cells to dried rat tail collagen augments the elevated levels of these mRNAs for the initial 1 to 2 h postplating; junB and c-myc mRNA levels then drop steeply, with junB returning to normal quiescence and the c-myc level remaining slightly elevated during the 3-day culture period. Levels of c-jun mRNA and AP-1 DNA binding activity, however, remain elevated from the outset, while C/EBP alpha mRNA expression is down-regulated, resulting in a decrease in the steady-state levels of the 42- and 30-kDa C/EBP alpha polypeptides and C/EBP alpha DNA binding activity. In contrast, C/EBP beta mRNA production remains at near-normal hepatic levels for 5 to 8 days of culture, although its DNA binding activity decreases severalfold during this time. Adhesion of hepatocytes to the EHS gel for the same period of time dramatically alters this program: it arrests growth and inhibits AP-1 DNA binding activity and the expression of c-jun, junB, and c-myc mRNAs, but, in addition, it restores C/EBP alpha mRNA and protein as well as C/EBP alpha and C/EBP beta DNA binding activities to the abundant levels present in freshly isolated hepatocytes. These changes are not due merely to growth inhibition, because suppression of hepatocyte proliferation on collagen by epidermal growth factor starvation or addition of transforming growth factor beta does not inhibit AP-1 activity or restore C/EBP alpha DNA binding activity to normal hepatic levels. These data suggest that expression of the normal hepatic phenotype requires that hepatocytes exist in a G0 state of growth arrest, facilitated here by adhesion of cells to the EHS gel, in order to express high levels of hepatic transcription factors such as C/EBP alpha.

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