MAPK/ERK通路
自噬
废气再循环1
生物
细胞生物学
基因敲除
癌症研究
内科学
p38丝裂原活化蛋白激酶
转录因子
内分泌学
激酶
医学
细胞培养
细胞凋亡
生物化学
遗传学
基因
作者
Man J. Livingston,Ming Zhang,Sang Ho Kwon,Jiankang Chen,Honglin Li,Santhakumar Manicassamy,Zheng Dong
出处
期刊:Autophagy
[Informa]
日期:2023-11-18
卷期号:: 1-22
被引量:3
标识
DOI:10.1080/15548627.2023.2281156
摘要
ABSTRACTMacroautophagy/autophagy contributes to maladaptive kidney repair by inducing pro-fibrotic factors such as FGF2 (fibroblast growth factor 2), but the underlying mechanism remains elusive. Here, we show that EGR1 (early growth response 1) was induced in injured proximal tubules after ischemic acute kidney injury (AKI) and this induction was suppressed by autophagy deficiency in inducible, renal tubule-specific atg7 (autophagy related 7) knockout (iRT-atg7 KO) mice. In cultured proximal tubular cells, TGFB1 (transforming growth factor beta 1) induced EGR1 and this induction was also autophagy dependent. Egr1 knockdown in tubular cells reduced FGF2 expression during TGFB1 treatment, leading to less FGF2 secretion and decreased paracrine effects on fibroblasts. ChIP assay detected an increased binding of EGR1 to the Fgf2 gene promoter in TGFB1-treated tubular cells. Both Fgf2 and Egr1 transcription was inhibited by FGF2 neutralizing antibody, suggesting a positive feedback for EGR1-mediated FGF2 autoregulation. This feedback was confirmed using fgf2-deficient tubular cells and fgf2-deficient mice. Upstream of EGR1, autophagy deficiency in mice suppressed MAPK/ERK (mitogen-activated protein kinase) activation in post-ischemic renal tubules. This inhibition correlated with SQSTM1/p62 (sequestosome 1) aggregation and its sequestration of MAPK/ERK. SQSTM1/p62 interacted with MAPK/ERK and blocked its activation during TGFB1 treatment in autophagy-deficient tubular cells. Inhibition of MAPK/ERK suppressed EGR1 and FGF2 expression in maladaptive tubules, leading to the amelioration of renal fibrosis and improvement of renal function. These results suggest that autophagy activates MAPK/ERK in renal tubular cells, which induces EGR1 to transactivate FGF2. FGF2 is then secreted into the interstitium to stimulate fibroblasts for fibrogenesis.Abbreviation: 3-MA: 3-methyladenine; ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB/β-actin: actin, beta; AKI: acute kidney injury; aa: amino acid; ATG/Atg: autophagy related; BUN: blood urea nitrogen; ChIP: chromatin immunoprecipitation; CKD: chronic kidney disease; CM: conditioned medium; COL1A1: collagen, type I, alpha 1; COL4A1: collagen, type IV, alpha 1; CQ: chloroquine; DBA: dolichos biflorus agglutinin; EGR1: early growth response 1; ELK1: ELK1, member of ETS oncogene family; FGF2: fibroblast growth factor 2; FN1: fibronectin 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAVCR1/KIM-1: hepatitis A virus cellular receptor 1; IP: immunoprecipitation; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2K/MEK: mitogen-activated protein kinase kinase; MAPK: mitogen-activated protein kinase; NFKB: nuclear factor kappa B; PB1: Phox and Bem1; PFT: pifithrin α; PPIB/cyclophilin B: peptidylprolyl isomerase B; RT-qPCR: real time-quantitative PCR; SQSTM1/p62: sequestosome 1; TGFB1/TGF-β1: transforming growth factor beta 1; VIM: vimentinKEYWORDS: Interstitial fibrosisischemic acute kidney injurykidney repairSQSTM1/p62tubulo-interstitial communication AcknowledgementsWe thank Dr. Masaaki Komatsu and Dr. Robert Koester for providing Atg7flox/flox mice and double transgenic Pax8-rtTA±, LC1± mice respectively that were used in this study to generate the inducible, renal tubule-specific Atg7 knockout mouse model.Disclosure statementNo potential conflict of interest was reported by the author(s).Data availability statementThe authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.Supplementary materialSupplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2023.2281156Additional informationFundingThe work was supported by the National Institutes of Health of USA [5R01DK058831]; Department of Veterans Affairs of USA [1TK6BX005236]; Department of Veterans Affairs of USA [I01 BX000319]; National Institutes of Health of USA [5R01DK087843].
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