Polycystic kidney disease and therapeutic approaches

Gao

American Journal of Physiology-Renal Physiology

et al. 2012

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by massive enlargement of fluid-filled cysts in the kidney. However, there is no effective therapy yet for this disease. To examine whether ginkgolide B, a natural compound, inhibits cyst development, a Madin-Darby canine kidney (MDCK) cyst model, an embryonic kidney cyst model, and a PKD mouse model were used. Interestingly, ginkgolide B significantly inhibited MDCK cyst formation dose dependently, with up to 69% reduction by 2 μM ginkgolide B. Ginkgolide B also significantly inhibited cyst enlargement in the MDCK cyst model, embryonic kidney cyst model, and PKD mouse model. To determine the underlying mechanisms, the effect of ginkgolide B on MDCK cell viability, proliferation, apoptosis, chloride transporter CFTR activity, and intracellular signaling pathways were also studied. Ginkgolide B did not affect cell viability, proliferation, and expression and activity of the chloride transporter CFTR that mediates cyst fluid secretion. Ginkgolide B induced cyst cell differentiation and altered the Ras/MAPK signaling pathway. Taken together, our results demonstrate that ginkgolide B inhibits renal cyst formation and enlargement, suggesting that ginkgolide B might be developed into a novel candidate drug for ADPKD.

mentioning

confidence: 99%

Ginkgolide B inhibits renal cyst development in in vitro and in vivo cyst models

Gao

American Journal of Physiology-Renal Physiology

et al. 2012

American Journal of Physiology-Renal Physiology

“…In particular, efforts have been directed toward interfering with the intracellular pathways governing cyst growth. A more comprehensive review of this topic can be found elsewhere (38,139,160,163,190,206,209,215). Among the approaches to slowing cyst growth is the vasopressin V2 receptor antagonist tolvaptan, a drug that blocks the renal effect of AVP on cAMP production.…”

Section: Potential Therapies For Adpkdmentioning

confidence: 99%

Novel role of ouabain as a cystogenic factor in autosomal dominant polycystic kidney disease

Blanco

Wallace

2013

The classic role of the Na-K-ATPase is that of a primary active transporter that utilizes cell energy to establish and maintain transmembrane Na(+) and K(+) gradients to preserve cell osmotic stability, support cell excitability, and drive secondary active transport. Recent studies have revealed that Na-K-ATPase located within cholesterol-containing lipid rafts serves as a receptor for cardiotonic steroids, including ouabain. Traditionally, ouabain was viewed as a toxin produced only in plants, and it was used in relatively high concentrations to experimentally block the pumping action of the Na-K-ATPase. However, the new and unexpected role of the Na-K-ATPase as a signal transducer revealed a novel facet for ouabain in the regulation of a myriad of cell functions, including cell proliferation, hypertrophy, apoptosis, mobility, and metabolism. The seminal discovery that ouabain is endogenously produced in mammals and circulates in plasma has fueled the interest in this endogenous molecule as a potentially important hormone in normal physiology and disease. In this article, we review the role of the Na-K-ATPase as an ion transporter in the kidney, the experimental evidence for ouabain as a circulating hormone, the function of the Na-K-ATPase as a signal transducer that mediates ouabain's effects, and novel results for ouabain-induced Na-K-ATPase signaling in cystogenesis of autosomal dominant polycystic kidney disease.

“…Target prediction algorithms reveal that the known genes involved in cytogenesis are likely under control of multiple microRNAs; some of these microRNA – mRNA target interactions have been evaluated experimentally [26–28]. Indeed, microRNAs contribute to cystogenesis via regulation of polycystic liver disease-related genes, Pkd1 and Pkd2 .…”

Section: Polycystic Liver Diseasesmentioning

confidence: 99%

MicroRNAs in Cholangiopathies

et al. 2014

Cholangiocytes, the cells lining bile ducts, comprise a small fraction of the total cellular component of the liver, yet perform the essential role of bile modification and transport of biliary and blood constituents. Cholangiopathies are a diverse group of biliary disorders with the cholangiocyte as the target cell; the etiopathogenesis of most cholangiopathies remains obscure. MicroRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. These small RNAs may not only be involved in the etiopathogenesis of disease, but are showing promise as diagnostic and prognostic tools. In this brief review, we summarize recent work regarding the role of microRNAs in the etiopathogenesis of several cholangiopathies, and discuss their utility as prognostic and diagnostic tools.