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

被引：55

作者：

Ding, Hao ^{[1
]}

Bai, Feng ^{[1
,2
,3
]}

Cao, Hongdi ^{[1
]}

Xu, Jing ^{[1
]}

Fang, Li ^{[4
]}

Wu, Jining ^{[1
]}

Yuan, Qi ^{[1
]}

Zhou, Yang ^{[1
]}

Sun, Qi ^{[1
]}

He, Weichun ^{[1
]}

Dai, Chunsun ^{[1
]}

Zen, Ke ^{[5
]}

Jiang, Lei ^{[1
]}

Yang, Junwei ^{[1
]}

机构：

[1] Nanjing Med Univ, Affiliated Hosp 2, Ctr Kidney Dis, Nanjing 210003, Jiangsu, Peoples R China

[2] Xuzhou Med Univ, Huaian Hosp, Dept Endocrinol & Metab, Huaian, Peoples R China

[3] Huaian Second Peoples Hosp, Huaian, Peoples R China

[4] Nantong Univ, Affiliated Hosp, Dept Nephrol, Nantong, Peoples R China

[5] Nanjing Univ, Adv Inst Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing, Jiangsu, Peoples R China

来源：

ANTIOXIDANTS & REDOX SIGNALING | 2018年 / 29卷 / 07期

基金：

美国国家科学基金会; 中国国家自然科学基金;

关键词：

cAMP; phosphodiesterases; mitochondrial biogenesis; renal fibrosis; TO-MESENCHYMAL TRANSITION; DEPENDENT PROTEIN-KINASE; PHOSPHODIESTERASE ISOZYMES; OXIDATIVE STRESS; DISEASE PROGRESSION; RECEPTOR AGONIST; BINDING PROTEIN; CAMP; EPAC; EXOSOMES;

D O I：

10.1089/ars.2017.7041

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

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)-beta 1-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-beta and PGC-1 alpha expression and protect the mitochondrial function and structure of PTCs under TGF-beta 1 stimulation. The antifibrotic role of rolipram in renal fibrosis relies on C/EBP-beta and PGC-1 alpha 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-beta/PGC1-alpha and mitochondrial biogenesis.

引用

页码：637 / 652

页数：16

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