phenanthrenes 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

Topics: Adult; Diterpenes; Epoxy Compounds; Female; Humans; Male; Medicine, East Asian Traditional; Middle Aged; Phenanthrenes; Phytotherapy; Polycystic Kidney, Autosomal Dominant; Proteinuria; Treatment Outcome; Tripterygium

Autosomal dominant polycystic kidney disease (ADPKD), a major cause of end-stage renal failure, results from genetic mutation of either polycystin-1 (Pkd1) or polycystin-2 (Pkd2). In order to develop novel therapies to treat the advancement of disease progression, numerous rodent models of different genetic backgrounds are available to study cyst development.. Here, a Pkd1-floxed inducible mouse model using the interferon responsive Mx1Cre-recombinase was utilized to test the effect of the small molecule triptolide. Relative to other Pkd1 inactivation models, cyst progression in this neonatal to adult transition model is attenuated. Following the characterization of inducible cyst formation in these mice, the development of kidney cysts from triptolide or vehicle-treated animals was analysed.. Although Pkd1 deletion on postnatal Days P10 and P12 resulted in numerous cysts by P35, daily injections with triptolide beginning on Day P16 significantly reduced the total number of cysts per kidney, with a pronounced effect on the number of microcysts and the overall cystic burden. Additionally, renal function as assessed by blood urea nitrogen levels was also improved in triptolide-treated mice at both the P22 and P35 time points. As the Pkd1(flox/flox);Mx1Cre model has not been previously used for drug development studies, the feasibility of a 6-month adult Pkd1 inactivation study was also tested. While kidney cyst formation was minimal and focal in nature, livers of these Pkd1-deficient mice were severely cystic, enlarged and pale.. These results suggest that the Pkd1(flox/flox);Mx1Cre model of ADPKD is amenable to short-term kidney cyst formation drug studies; however, it may be problematic for long-term therapeutic research where widespread liver cysts and fibrosis could compromise drug metabolism.

Topics: Aging; Animals; Antineoplastic Agents, Alkylating; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Disease Progression; Diterpenes; Epoxy Compounds; GTP-Binding Proteins; Integrases; Kidney; Mice; Mice, Mutant Strains; Mutation; Myxovirus Resistance Proteins; Phenanthrenes; Polycystic Kidney, Autosomal Dominant; Time Factors; TRPP Cation Channels

Mutations in PKD1 result in autosomal dominant polycystic kidney disease, which is characterized by increased proliferation of tubule cells leading to cyst initiation and subsequent expansion. Given the cell proliferation associated with cyst growth, an attractive therapeutic strategy has been to target the hyperproliferative nature of the disease. We previously demonstrated that the small molecule triptolide induces cellular calcium release through a polycystin-2-dependent pathway, arrests Pkd1(-/-) cell growth, and reduces cystic burden in Pkd1(-/-) embryonic mice. To assess cyst progression in neonates, we used the kidney-specific Pkd1(flox/-);Ksp-Cre mouse model of autosomal dominant polycystic kidney disease, in which the burden of cysts is negligible at birth but then progresses rapidly over days. The number, size, and proliferation rate of cysts were examined. Treatment with triptolide significantly improved renal function at postnatal day 8 by inhibition of the early phases of cyst growth. Because the proliferative index of kidney epithelium in neonates versus adults is significantly different, future studies will need to address whether triptolide delays or reduces cyst progression in the Pkd1 adult model.

Topics: Animals; Animals, Newborn; Antineoplastic Agents, Alkylating; Diterpenes; Epoxy Compounds; Mice; Mice, Transgenic; Phenanthrenes; Polycystic Kidney, Autosomal Dominant