Abstract
Background: Renal tubulointerstitial fibrosis is the key pathological feature in chronic kidney diseases (CKDs) with no satisfactory therapies in clinic. Cilomilast is a second-generation, selective phosphodiesterase-4 inhibitor, but its role in renal tubulointerstitial fibrosis in CKD remains unclear.Material and Methods: Cilomilast was applied to the mice with unilateral ureteric obstruction (UUO) and renal fibroblast cells (NRK-49F) stimulated by TGF-β1. Renal tubulointerstitial fibrosis and inflammation after UUO or TGF-β1 stimulation were examined by histology, Western blotting, real-time PCR and immunohistochemistry. KIM-1 and NGAL were detected to evaluate tubular injury in UUO mice.Results: In vivo, immunohistochemistry and western blot data demonstrated that cilomilast treatment inhibited extracellular matrix deposition, profibrotic gene expression, and the inflammatory response. Furthermore, cilomilast prevented tubular injury in UUO mice, as manifested by reduced expression of KIM-1 and NGAL in the kidney. In vitro, cilomilast attenuated the activation of fibroblast cells stimulated by TGF-β1, as shown by the reduced expression of fibronectin, α-SMA, collagen I, and collagen III. Cilomilast also inhibited the activation of TGF-β1-Smad2/3 signaling in TGF-β1-treated fibroblast cells.Conclusion: The findings of this study suggest that cilomilast is protective against renal tubulointerstitial fibrosis in CKD, possibly through the inhibition of TGF-β1-Smad2/3 signaling, indicating the translational potential of this drug in treating CKD.
Highlights
Chronic kidney disease (CKD) has become a major public health problem in many countries
Mice were anesthetized with 2% isoflurane, and the left ureter was Abbreviations: CKD, chronic kidney disease; UUO, unilateral ureteric obstruction; ESRD, end-stage renal diseases; cAMP, cyclic adenosine monophosphate; COPD, chronic obstructive pulmonary disease; IHC, immunohistochemistry; ECM, extracellular matrix; Phosphodiesterase 4 (PDE4), phosphodiesterase 4; Transforming growth factor-β1 (TGF-β1), transforming growth factor-β1; FN, fibronectin; α-SMA, α-smooth muscle actin; Col-I, collagen I; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase-associated lipocalin; SEM, standard errors of the mean
We used a UUO model to explore the effect of cilomilast treatment on renal tubulointerstitial fibrosis (Figure 1A)
Summary
Chronic kidney disease (CKD) has become a major public health problem in many countries. A report showed that one PDE4 inhibitor, rolipram, played an antifibrotic role in CKD possibly via acting on C/EBPβ and PGC-1α in tubular epithelial cells [13]. Cilomilast is another PDE4 inhibitor that is currently being investigated in a phase III clinical trial for the treatment of chronic obstructive pulmonary disease (COPD). It has beneficial effects on COPD [14], tumors [15], acute lung injury [16], and acute kidney injury [12]. Cilomilast is a second-generation, selective phosphodiesterase-4 inhibitor, but its role in renal tubulointerstitial fibrosis in CKD remains unclear
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