PDE/cAMP/Epac/C/EBP-β Signaling Cascade Regulates Mitochondria Biogenesis of Tubular Epithelial Cells in Renal Fibrosis

Hao Ding;Feng Bai;Hongdi Cao;Jing Xu;Li Fang;Jining Wu;Qi Yuan;Yang Zhou;Qi Sun;Weichun He;Chunsun Dai;Ke Zen;雷 江;Junwei Yang

Nanjing Medical University;Xuzhou Medical University;Nantong University;Nanjing University;China Association for Science and Technology

发表时间:2018-9-1

期 刊:Antioxidants and Redox Signaling

语 言:English

U R L: http://www.scopus.com/inward/record.url?scp=85050668516&partnerID=8YFLogxK

摘要

Aims: Cyclic adenosine 3′5′-monophosphate (cAMP) is a universal second messenger that plays an important role in intracellular signal transduction. cAMP is synthesized by adenylate cyclases from adenosine triphosphate and terminated by the phosphodiesterases (PDEs). In the present study, we investigated the role of the cAMP pathway in tubular epithelial cell mitochondrial biogenesis in the pathogenesis of renal fibrosis. Results: We found that the cAMP levels were decreased in fibrotic kidney tissues, and replenishing cAMP could ameliorate tubular atrophy and extracellular matrix deposition. The downregulation of cAMP was mainly attributed to the increased PDE4 expression in tubular epithelial cells. The inhibition of PDE4 by PDE4 siRNA or the specific inhibitor, rolipram, attenuated unilateral ureteral obstruction-induced renal interstitial fibrosis and transforming growth factor (TGF)-β1-stimulated primary tubular epithelial cell (PTC) damage. The Epac1/Rap1 pathway contributed to the main effect of cAMP on renal fibrosis. Rolipram could restore C/EBP-β and PGC-1α expression and protect the mitochondrial function and structure of PTCs under TGF-β1 stimulation. The antifibrotic role of rolipram in renal fibrosis relies on C/EBP-β and PGC-1α expression in tubular epithelial cells. Innovation and Conclusion: The results of the present study indicate that cAMP signaling regulates the mitochondrial biogenesis of tubular epithelial cells in renal fibrosis. Restoring cAMP by the PDE4 inhibitor rolipram may ameliorate renal fibrosis by targeting C/EBP-β/PGC1-α and mitochondrial biogenesis. Antioxid. Redox Signal. 29, 637-652.

关键词

cAMP
mitochondrial biogenesis
phosphodiesterases
renal fibrosis

相关科学

生物化学、遗传学和分子生物学
生物化学
细胞生物学
临床生物化学
分子生物学
生理学

文献指纹

化合物

Cyclic AMP

Mitochondria

Epithelial Cells

Phosphoric Diester Hydrolases

Rolipram

Transforming Growth Factors

Signal transduction

Phosphodiesterase 4 Inhibitors

Oxidation-Reduction

Second Messenger Systems

Adenylyl Cyclases

Tissue

Small Interfering RNA

Adenosine Triphosphate

医学与生命科学

Phosphoric Diester Hydrolases

Cyclic AMP

Mitochondria

Fibrosis

Epithelial Cells

Rolipram

Kidney

Organelle Biogenesis

Transforming Growth Factors

Phosphodiesterase 4 Inhibitors

Ureteral Obstruction

Second Messenger Systems

Adenylyl Cyclases

Oxidation-Reduction

Atrophy

Extracellular Matrix

Small Interfering RNA

Signal Transduction

Adenosine Triphosphate

Down-Regulation

期刊度量

Scopus度量

年份 CiteScore SJR SNIP
1996
1997
1998
1999
2000 0.489 0.251
2001 0.537 0.311
2002 1.071 0.621
2003 1.424 0.738
2004 1.739 0.895
2005 1.869 0.866
2006 1.946 0.896
2007 2.69 1.242
2008 3.041 1.384
2009 3.184 1.667
2010 3.117 1.676
2011 11 3.353 1.932
2012 13 3.434 1.764
2013 13.3 3.395 1.857
2014 13.2 3.137 1.742
2015 13.4 3.066 1.597
2016 15.7 2.897 1.678
2017 14.6 2.607 1.586
2018 11 2.151 1.439
2019 10.7 2.163 1.56
2020 11.5

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