LAUSR

Renal fibrosis is the common final pathway of various chronic kidney diseases (CKDs), irrespective of the initial causes of nephropathy. Decline of renal function, glomerular filtration rate, has been exhibited to be highly associated with the progression of tubulointerstitial fibrosis.1 Fibrosis is considered to occur via a variety of events, which increase the level of transforming growth factor‐β1 (TGF‐β1), a profibrotic cytokine, in renal tissue. TGF‐β1 induces the emergence of myofibroblasts, myofibroblast transdifferentiation, followed by the accumulation of extracellular matrices such as type I collagen, ie, fibrosis.2 The myofibroblast is characterized by the expression of α‐smooth muscle actin (α‐SMA) in the cytoplasm. Thus, α‐SMA is generally accepted as a marker of fibrosis.3, 4, 5 Dipyridamole is in clinical use as an anti‐platelet agent. The reno‐protective effects exerted by dipyridamole have been demonstrated in animal models6 and humans with the early stage CKD.7 In almost all of these experiments and studies, the amelioration effects of dipyridamole on proteinuria were indicated to be mediated by the repression of platelet aggregation which was generally recognized in CKD. Dipyridamole increases cAMP levels by inhibiting phosphodiesterase in a variety of cells including platelets. The cAMP acts through three pathways of its downstream: protein kinase A (PKA), exchange factor directly activated by cAMP (Epac),8 and cyclic nucleotide‐gated (CNG) ion channels.9 In the Epac pathway, the increased intracellular cAMP binds to Epac, a guanine nucleotide exchange factor, followed by activation of the low molecular weight G‐protein Rap. Epac contributes to numerous pathophysiological processes, including proliferation, differentiation, cell adhesion, cell junction formation, and exocytosis. In the present study, the effects of dipyridamole against renal fibrosis, the late stage CKD, were investigated in a system without platelet aggregation. In addition, the mechanism by which dipyridamole exerted its effects was examined.