Epac activation ameliorates tubulointerstitial inflammation in diabetic nephropathy
- 8 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Pharmacologica Sinica
- Vol. 43 (3), 659-671
- https://doi.org/10.1038/s41401-021-00689-2
Abstract
Tubulointerstitial inflammation plays an important role in the progression of diabetic nephropathy (DN), and tubular epithelial cells (TECs) are crucial promoters of the inflammatory cascade. Exchange protein activated by cAMP (Epac) has been shown to suppress the angiotensin II (Ang-II)-induced release of inflammatory cytokines in tubular cells. However, the role of Epac in TEC-mediated tubulointerstitial inflammation in DN remains unknown. We found that administering the Epac agonist 8-pCPT-2′-O-Me-cAMP (8-O-cAMP) to db/db mice inhibited tubulointerstitial inflammation characterized by macrophage infiltration and increased inflammatory cytokine release and consequently alleviated tubulointerstitial fibrosis in the kidney. Furthermore, 8-O-cAMP administration restored CCAAT/enhancer binding protein β (C/EBP-β) expression and further upregulated the expression of Suppressor of cytokine signaling 3 (SOCS3), while inhibiting p-STAT3, MCP-1, IL-6, and TNF-α expression in the kidney cortex in db/db mice. And in vitro study showed that macrophage migration and MCP-1 expression induced by high glucose (HG, 30 mM) were notably reduced by 8-O-cAMP in human renal proximal tubule epithelial (HK-2) cells. In addition, 8-O-cAMP treatment restored C/EBP-β expression in HK-2 cells and promoted C/EBP-β translocation to the nucleus, where it transcriptionally upregulated SOCS3 expression, subsequently inhibiting STAT3 phosphorylation. Under HG conditions, siRNA-mediated knockdown of C/EBP-β or SOCS3 in HK-2 cells partially blocked the inhibitory effect of Epac activation on the release of MCP-1. In contrast, SOCS3 overexpression inhibited HG-induced activation of STAT3 and MCP-1 expression in HK-2 cells. These findings indicate that Epac activation via 8-O-cAMP ameliorates tubulointerstitial inflammation in DN through the C/EBP-β/SOCS3/STAT3 pathway.Keywords
This publication has 59 references indexed in Scilit:
- Inflammation in Diabetic NephropathyMediators of Inflammation, 2012
- cAMP signalling protects proximal tubular epithelial cells from cisplatin‐induced apoptosis via activation of EpacBritish Journal of Pharmacology, 2011
- Epac-Rap Signaling Reduces Cellular Stress and Ischemia-induced Kidney FailureJournal of the American Society of Nephrology, 2011
- Suppressors of Cytokine Signaling Abrogate Diabetic NephropathyJournal of the American Society of Nephrology, 2010
- PKA-dependent potentiation of glucose-stimulated insulin secretion by Epac activator 8-pCPT-2′-O-Me-cAMP-AM in human islets of LangerhansAmerican Journal of Physiology-Endocrinology and Metabolism, 2010
- Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathyKidney International, 2009
- C/EBP-β Modulates Transcription of Tubulointerstitial Nephritis Antigen in Obstructive UropathyJournal of the American Society of Nephrology, 2009
- SOCS proteins, cytokine signalling and immune regulationNature Reviews Immunology, 2007
- Exchange Protein Activated by Cyclic AMP (Epac)-Mediated Induction of Suppressor of Cytokine Signaling 3 (SOCS-3) in Vascular Endothelial CellsMolecular and Cellular Biology, 2006
- Suppressors of cytokine signaling in health and diseasePediatric Nephrology, 2005