Epac activation ameliorates tubulointerstitial inflammation in diabetic nephropathy.

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.

• Authors: Wen-Xia Yang, Yu Liu, Shu-Min Zhang, Hua-Fen Wang, Yi-Fei Liu, Jia-Lu Liu, Xiao-Hui Li, Meng-Ru Zeng, Yu-Zhang Han, Fu-You Liu, Lin Sun, Li Xiao
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 43 Issue 3 Pg. 659-671 (Mar 2022) ISSN: 1745-7254 [Electronic] United States
• PMID: 34103688 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to CPS and SIMM.

Chemical References

• 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate
• CCAAT-Enhancer-Binding Protein-beta
• Cytokines
• Guanine Nucleotide Exchange Factors
• Inflammation Mediators
• STAT3 Transcription Factor
• Suppressor of Cytokine Signaling 3 Protein
• Cyclic AMP

Topics

• Animals
• CCAAT-Enhancer-Binding Protein-beta (drug effects)
• Cyclic AMP (analogs & derivatives, pharmacology)
• Cytokines (drug effects)
• Diabetic Nephropathies (pathology)
• Guanine Nucleotide Exchange Factors (agonists)
• Humans
• Inflammation (pathology)
• Inflammation Mediators (metabolism)
• Kidney Tubules (drug effects)
• Macrophages (drug effects)
• Mice
• Mice, Inbred C57BL
• Random Allocation
• STAT3 Transcription Factor (drug effects)
• Signal Transduction (drug effects)
• Suppressor of Cytokine Signaling 3 Protein (drug effects)
• Up-Regulation