The Pharmacological Study Of 1-Indanone Retarding Renal Cysts Progression In ADPKD

Autosomal dominant polycystic kidney disease(ADPKD)is the most common hereditary renal disease,with a prevalence of 1/2500～1/1000 worldwide.ADPKD is characterized by excessive proliferation of renal epithelial cells and progressive fluid-filled cysts in bilateral kidneys.ADPKD is caused by the mutations of Pkd1 or Pkd2 gene.Pkd1 and Pkd2 encode polycystin(PC)PC1 and PC2 respectively,which form a polycystin complex and localize on primary cilia.Primary cilia are organelles that protrude from the cell surface and function as sensors for fluid flow,transducing signaling from the environment into the cell.PC1 converts ciliary movements caused by fluid flow into mechanical signals,which in turn are converted into calcium signals mediated by PC2.Defects of polycystin or primary cilia affect intracellular calcium and downstream signal transduction,resulting in abnormal proliferation of renal tubular epithelial cells and secretion of cystic fluid,which leads to the formation of renal cysts.Most of ADPKD patients develop into end-stage renal disease(ESRD)around the age of60 requiring kidney dialysis or transplantation,which imposes a serious burden to family and society.The clinical treatment of ADPKD is very limited.At present,there is only tolvaptan,a vasopressin type 2 receptor antagonist that is approved as a therapeutic medication for ADPKD.However,the patients with long-term use of tolvaptan will face a high risk of liver injury.Therefore,there is still an urgent need to discover therapeutic drugs that are effective against ADPKD with fewer adverse effects.Intriguingly,ADPKD has extensive similar pathological features with solid tumors,including excessive cell proliferation,extracellular matrix(ECM)remodeling,abnormal epithelial cellular polarity and differentiation,dysregulated energetics and alterations in primary cilia.Previous studies have found that some natural products with anti-tumor activity,such as Ganoderma triterpenes and Cardamonin,significantly slowed down the development of renal cyst in ADPKD.Primary cilia are involved in many crucial biological processes as organ development,cell polarity and cell proliferation.Abnormal elongated primary cilia of cyst epithelial cells have been found in a variety of ADPKD mouse models and in ADPKD patients.It suggests that structural defect of primary cilium is the trigger of cyst formation in ADPKD.However,there are still controversies about the role of primary cilium in cyst progression in ADPKD.Therefore,we investigated primary cilium length in ADPKD and whether normalizing cilium length could be an effective treatment for ADPKD.We screened out 1-indanone from the natural product library through PKD cyst models both in vitro and in vivo.It inhibited abnormal elongated primary cilia of cystic epithelial cells in Pkd1 knockout mice and human ADPKD cystic epithelial cells by promoting the polymerization of tubulin.The expression of primary cilia anterograde transporter IFT88 and motor protein KIF3 A and KIF3 B were down-regulated as well.In addition,it also downregulated the expression of cilia co-ordinated signaling pathways Hedgehog and Wnt/β-catenin signals.Thus,1-indanone suppressed the abnormal proliferation caused by excessive activation of c AMP-PKA and downstream m TOR and Ras/MAPK signaling pathways.Consequently,1-indanone suppressed the progression of renal cysts and significantly reduced the renal cystic index.Therefore,1-indanone is expected to become a therapeutic drug for ADPKD,and modulating cilium length of cystic epithelial cells may become an effective treatment strategy against ADPKD.