Autosomal dominant polycystic kidney disease (ADPKD) is characterized by perturbations in extracellular matrix synthesis, cellular polarity, gene expression, and proliferative potential of the epithelial cells lining renal cysts. The mechanisms whereby these cells express a partially dedifferentiated phenotype have remained enigmatic despite the identification of the causative genetic lesions. A comprehensive assessment of epithelial cell architecture, molecular trafficking, cellular plasticity, and extracellular matrix profile was therefore undertaken. These analyses revealed several anomalies as candidate factors that undoubtedly undermine the integrity of ADPKD tissue. Within explanted ADPKD cells the cytoskeletal networks were biochemically or structurally immature. Moreover, both the adherens junction protein E-cadherin and basolateral targeting patch components were depleted from the basolateral ADPKD cell surface. These derangements correlated with impaired vectorial trafficking: while apical transport proceeded effectively, basolateral trafficking in the diseased cells was inefficient. Stalling of traffic along the basolateral exocytic route was evident as an accumulation of exocytic cargo within the dilated ADPKD cell Golgi and the redistribution of several components of the basolateral trafficking machinery. The architectural and behavioral disturbances in the mutant cells prompted an examination of the interplay between cellular phenotype and extracellular matrix. Deprived of native environmental cues by explantation into monolayer culture, diseased cells were unable to fully redifferentiate. Furthermore, while normal kidney cells formed branching tubules in collagen-I matrices, ADPKD cells assembled spherical cysts or failed altogether to organize into multicellular aggregates. Remarkably, ADPKD cells cultured within purified native extracellular matrix successfully completed branching morphogenesis, demonstrating that genetic lesions did not completely abolish the morphogenetic potential of these cells. The dissimilar behavior of ADPKD cells cultured in different matrices suggested that the extracellular matrix in ADPKD tissue is permissive for cystogenesis. The aberrant deposition of a novel matrix microfibril protein within the basement membrane circumscribing ADPKD cysts represents an environmental cue that likely exacerbates atypical cellular behavior. Considered together, the results presented herein imply the existence of a pathological circuit initiated by the acquisition of genetic mutations and perpetuated by cellular dedifferentiation, ultimately leading to tissue dysmorphogenesis and the degeneration of renal epithelia.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a highly prevalent hereditary renal disorder in which fluid-filled cysts are appeared in both kidneys. Main causative genes of ADPKD are PKD1 and PKD2, encoding for polycystin-1 (PC1) and polycystin-2 (PC2) respectively. Those proteins are localized on primary cilia and function as mechanosensor in response to the fluid flow, translating mechanistic stimuli into calcium signaling. With mutations either of PKD1 or PKD2, hyper-activated renal tubular epithelial cell proliferation is observed, followed by disrupted calcium homeostasis and aberrant intracellular cyclic AMP (cAMP) accumulation. Increased cell proliferation with fluid secretion leads to the development of thousands of epithelial-lined, fluid-filled cysts in kidneys. It is also accompanied by interstitial inflammation, fibrosis, and finally reaching end-stage renal disease (ESRD). In human ADPKD, the age at which renal failure typically occurs is later in life, however no specific targeted medications are available to cure ADPKD. Recently, potential therapeutic targets or surrogate diagnostic biomarkers for ADPKD are proposed with the advances in the understanding of ADPKD pathogenesis, and some of them were attempted for clinical trials. Herein, we will summarize genetic and epi-genetic molecular mechanisms in ADPKD progression, and overview the currently available biomarkers or potential therapeutic reagents suggested.

This is a book about renal cysts and cystic kidneys. Its contributors have created a resource of current information in a field that once aroused only curiosity, but that now stands at the leading edge of molecular nephrology. Its authorship includes 'oldtimers', who bring the wisdom of experience, and 'newcomers', whose presence attests to the contributions made by the investigative and technological advances of the past decade. Its text is organized to carry the reader from renal cyst to cystic renal disease. Each of its chapters defines or explores a challenge or an advance. Cells that line renal cysts are diverse in structure, type, and perhaps function. The cysts themselves lie within an interstitium that is not normal and may influence cyst development and growth. Experimental analogs of human disease offer increasing opportunities to basic researchers to examine, in sequence and under controlled circumstances, those events that favor nephron dilation, cyst growth and ultimate renal failure.

An algorithmic approach to interpreting renal pathology, updated in light of recent advances in understanding and new classification schemes.

This book reviews important aspects of polycystic kidney diseases, the latest scientific understanding of the diseases and syndromes, along with the therapies being developed. Cystic kidney diseases comprise a spectrum of genetic syndromes defined by renal cyst formation and expansion with variable extrarenal manifestations. The most prevalent disorder is the autosomal dominant polycystic kidney disease (ADPKD). It is the most common monogenetic disorder in humans and accounts for 4.4% of end-stage renal disease (ESRD) cases in the U.S. Patients inevitably progress to ESRD and require renal replacement therapy in the form of dialysis or transplantation. Through advancements in genomics and proteomics approaches, novel genes responsible for cystic diseases have been identified, further expanding our understanding of basic mechanisms of disease pathogenesis. The hallmark among all cystic genetic syndromes is the formation and growth of fluid-filled cysts, which originate from tubular epithelia of nephron segments. Cysts are the disease, and treatment strategies are being developed to target prevention or delay of cyst formation and expansion at an early stage, however no such therapy is currently approved.

This volume focuses on the investigatory methods applied to autosomal dominant polycystic kidney disease (ADPKD), one of the most common human genetic diseases. ADPKD is caused by mutations in PKD1 and TRPP2, two integral membrane proteins that function as receptor/ion channels in primary cilia of tubular epithelial cells. Thus, ADPKD belongs to ciliopathies, a group of disorders caused by abnormal cilia formation or function. This proposed book will cover the state-of-the-art methods ranging from molecular biology, biochemistry, electrophysiology, to tools in model animal studies. Key Features Explores the role of cilia in polycystic kidney disease Focuses on myriad state-of-the-art methods and techniques Reviews specific mutations integral to this autosomal genetic disease Includes discussions of model systems