PDE4 Inhibitors Regulate Mitochondrial Biosynthesis In Renal Interstitial Fibrosis

Renal fibrosis is inevitably progressive no matter what the initial insult is or whether the insult persists.In clinical settings,renal biopsy samples show that fibrotic lesions are initially local and scattered;however,expand and progress with the time being.In experimental fibrosis model induced by unilateral ureteral obstruction(UUO),the accelerated pathologic changes could hardly be explained by aggravated pressure caused by hydronephrosis after ligation.Here,we investigated whether cAMP level contributed to the progression of renal fibrosis.In this study,uuo model and cultured primary tubular cells were involved.Thus,it was reasonable to speculate that cAMP level from injured tubules contribute to the progression of renal fibrosis.We reported that The cAMP level in the renal tubular cells diminished fibrosis signaling by target EPAC protein.These results demonstrated that enhance cAMP level in tubular cells could alleviate renal tubular fibrosis by enhancing EPAC signaling in primary tubular cells.cAMP level among tubular epithelial cells might shed a new light and therapy target on the mechanism of progressive renal fibrosis.cAMP level contributes to tubulointerstitial fibrosis but its regulation in renal tubular cells remained unclear.PDE4 is a specific hydrolase of cAMP.Here,in fibrotic kidney induced by unilateral ureteral obstruction(UUO)or primary cultured renal tubular epithelial cells,we demonstrated that PDE4 b was involved in renal interstitial fibrosis.cAMP level in tubular segments isolated from kidney was markedly down-regulated after obstruction.However,the increase of PDE4 was increased in not only tubular segments,but also in primary cultured tubular epithelial cells incubated with TGF-?1.This study suggests that PDE4 inhibitor ameliorates renal interstitial fibrosis through improving mitochondrial biogenesis.This study highlights the importance of PDE4 inhibitor in renal fibrosis,demonstrates a new mechanism concerning mitochondrial biogenesis in fibrosis and will probably provide new therapeutic targets of renal fibrosis.