Hao Ding1, Feng Bai1,2, Hongdi Cao1, Jing Xu1, Li Fang3, Jining Wu1, Qi Yuan1, Yang Zhou1, Qi Sun1, Weichun He1, Chunsun Dai1, Ke Zen4, Lei Jiang1, Junwei Yang1. 1. 1 Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University , Nanjing, China . 2. 2 Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University and Huai'an Second People's Hospital , Huai'an, China . 3. 3 Department of Nephrology, Affiliated Hospital of Nantong University , Nantong, China . 4. 4 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University Advanced Institute of Life Sciences , Nanjing, China .
Abstract
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.
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.
Authors: Wai-Kin So; Hyoung Kyu Kim; Yingxian Chen; Seung Hun Jeong; Patrick Ka Kit Yeung; Billy C K Chow; Jin Han; Sookja K Chung Journal: Pflugers Arch Date: 2020-01-18 Impact factor: 3.657
Authors: Margaret A McBride; Allison M Owen; Cody L Stothers; Antonio Hernandez; Liming Luan; Katherine R Burelbach; Tazeen K Patil; Julia K Bohannon; Edward R Sherwood; Naeem K Patil Journal: Front Immunol Date: 2020-05-29 Impact factor: 7.561
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