cardamonin and Polycystic-Kidney--Autosomal-Dominant

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic kidney disorder that impairs renal functions progressively leading to kidney failure. The disease affects between 1:400 and 1:1000 ratio of the people worldwide. It is caused by the mutated PKD1 and PKD2 genes which encode for the defective polycystins. Polycystins mimic the receptor protein or protein channel and mediate aberrant cell signaling that causes cystic development in the renal parenchyma. The cystic development is driven by the increased cyclic AMP stimulating fluid secretion and infinite cell growth. In recent years, natural product-derived small molecules or drugs targeting specific signaling pathways have caught attention in the drug discovery discipline. The advantages of natural products over synthetic drugs enthusiast researchers to utilize the medicinal benefits in various diseases including ADPKD.. Overall, this review discusses some of the previously studied and reported natural products and their mechanisms of action which may potentially be redirected into ADPKD.

Topics: Antioxidants; Chalcones; Curcumin; Diterpenes; Diterpenes, Kaurane; Emodin; Epoxy Compounds; Estrogen Antagonists; Flavanones; Humans; Hypoglycemic Agents; Metformin; Phenanthrenes; Plant Extracts; Polycystic Kidney, Autosomal Dominant; Protein Kinase Inhibitors; Quercetin; Resveratrol

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic inherited kidney disease characterized by renal progressive fluid-filled cysts and interstitial fibrosis. Inhibiting renal cyst development and interstitial fibrosis has been proven effective in delaying the progression of ADPKD. The purpose of this study was to discover effective drugs from natural products for preventing and treating ADPKD. Candidate compounds were screened from a natural product library by virtual screening. The Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model, and orthologous mouse model of ADPKD were utilized to determine the pharmacological activities of the candidate compounds. Western blot and morphological analysis were used to investigate underlying mechanisms. The experimental results showed that 0.625, 2.5, and 10 μM cardamonin dose-dependently reduced formation and enlargement in MDCK cyst model. Cardamonin also significantly attenuated renal cyst enlargement in ex vivo mouse embryonic kidneys and PKD mouse kidneys. We found that cardamonin inhibited renal cyst development and interstitial fibrosis by downregulating the MAPK, Wnt, mTOR, and transforming growth factor-β/Smad2/3 signaling pathways. Cardamonin significantly inhibits renal cyst development and interstitial fibrosis, suggesting that cardamonin shows promise as a potential therapeutic drug for preventing and treating ADPKD.

Topics: Animals; Chalcones; Cysts; Dogs; Female; Fibrosis; Kidney; Madin Darby Canine Kidney Cells; Mice, Inbred ICR; Mice, Transgenic; Mitogen-Activated Protein Kinases; Polycystic Kidney, Autosomal Dominant; Signal Transduction; Smad2 Protein; Smad3 Protein; TOR Serine-Threonine Kinases; Transforming Growth Factor beta