A synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of chronic kidney disease and the fourth leading cause of end-stage kidney disease, accounting for over 50% of prevalent cases requiring renal replacement therapy. There is a pressing need for improved therapy for ADPKD. Recent insights into the pathophysiology of ADPKD revealed that cyst cells undergo metabolic changes that up-regulate aerobic glycolysis in lieu of mitochondrial respiration for energy production, a process that ostensibly fuels their increased proliferation.

Polycystic Kidney Disease Drug Development: A Conference Report.

Autosomal dominant polycystic kidney disease (ADPKD) is part of a spectrum of inherited diseases that also includes autosomal recessive polycystic kidney disease, autosomal dominant polycystic liver disease, and an expanding group of recessively inherited disorders collectively termed hepatorenal fibrocystic disorders. ADPKD is the most common monogenic disorder frequently leading to chronic kidney failure with an estimated prevalence of 12 million people worldwide. Currently, only one drug (tolvaptan) has been approved by regulatory agencies as disease-modifying therapy for ADPKD, but, given its mechanism of action and side effect profile, the need for an improved therapy for ADPKD remains a priority.

XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in Pkd1 and Pkd2. They encode the polytopic integral membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are expressed on primary cilia. Formation of kidney cysts in ADPKD starts when a somatic second hit mechanism inactivates the wild-type Pkd allele.

Disrupting polycystin-2 EF hand Ca affinity does not alter channel function or contribute to polycystic kidney disease.

Approximately 15% of autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in encodes polycystin-2, which forms an ion channel in primary cilia and endoplasmic reticulum (ER) membranes of renal collecting duct cells. Elevated internal Ca modulates polycystin-2 voltage-dependent gating and subsequent desensitization - two biophysical regulatory mechanisms that control its function at physiological membrane potentials. Here, we refute the hypothesis that Ca occupancy of the polycystin-2 intracellular EF hand is responsible for these forms of channel regulation, and, if disrupted, results in ADPKD.

Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of in Collecting Ducts.

Background: encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of in all distal nephron segments in embryonic mouse kidney results in polycystin-1-mediated polycystic kidney disease (PKD). It also activates the Ire1-Xbp1 branch of the unfolded protein response, producing Xbp1s, the active transcription factor promoting expression of specific genes to alleviate endoplasmic reticulum stress.

Isolated polycystic liver disease genes define effectors of polycystin-1 function.

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B.

Isolated polycystic liver disease genes define effectors of polycystin-1 function.

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B.

Is it Time to Fold the Cysts Away?

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2, encoding polycystin-1 and polycystin-2, respectively. Optimizing the folding environment for polycystin-1 missense mutations may have a critical effect on the progression of ADPKD in animal models and could potentially lead to tangible therapeutic options for subgroups of ADPKD patients.

Hepatocystin is Essential for TRPM7 Function During Early Embryogenesis.

Mutations in protein kinase C substrate 80K-H (PRKCSH), which encodes for an 80 KDa protein named hepatocystin (80K-H, PRKCSH), gives rise to polycystic liver disease (PCLD). Hepatocystin functions as the noncatalytic beta subunit of Glucosidase II, an endoplasmic reticulum (ER)-resident enzyme involved in processing and quality control of newly synthesized glycoproteins. Patients harboring heterozygous germline mutations in PRKCSH are thought to develop renal cysts as a result of somatic loss of the second allele, which subsequently interferes with expression of the TRP channel polycystin-2 (PKD2).

Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes.

Podocytes are terminally differentiated epithelial cells that reside along the glomerular filtration barrier. Evidence suggests that after podocyte injury, endoplasmic reticulum stress response is activated, but the molecular mechanisms involved are incompletely defined. In a mouse model, we confirmed that podocyte injury induces endoplasmic reticulum stress response and upregulated unfolded protein response pathways, which have been shown to mitigate damage by preventing the accumulation of misfolded proteins in the endoplasmic reticulum.

Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity.

The HSP40 cochaperone SEC63 is associated with the SEC61 translocon complex in the ER. Mutations in the gene encoding SEC63 cause polycystic liver disease in humans; however, it is not clear how altered SEC63 influences disease manifestations. In mice, loss of SEC63 induces cyst formation both in liver and kidney as the result of reduced polycystin-1 (PC1).

Altered trafficking and stability of polycystins underlie polycystic kidney disease.

The most severe form of autosomal dominant polycystic kidney disease occurs in patients with mutations in the gene (PKD1) encoding polycystin-1 (PC1). PC1 is a complex polytopic membrane protein expressed in cilia that undergoes autoproteolytic cleavage at a G protein-coupled receptor proteolytic site (GPS). A quarter of PKD1 mutations are missense variants, though it is not clear how these mutations promote disease.

N-glycosylation determines the abundance of the transient receptor potential channel TRPP2.

Glycosylation plays a critical role in the biogenesis and function of membrane proteins. Transient receptor potential channel TRPP2 is a nonselective cation channel that is mutated in autosomal dominant polycystic kidney disease. TRPP2 has been shown to be heavily N-glycosylated, but the glycosylation sites and the biological role of N-linked glycosylation have not been investigated.

Steviol retards renal cyst growth through reduction of CFTR expression and inhibition of epithelial cell proliferation in a mouse model of polycystic kidney disease.

Cyst enlargement in autosomal dominant polycystic kidney disease (ADPKD) is associated with cAMP-activated proliferation of cyst-lining epithelial cells and transepithelial fluid secretion into the cyst lumen via cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel leading to renal failure for which no effective treatment is currently available. We previously reported that steviol retards Madin-Darby canine kidney (MDCK) cyst enlargement by inhibiting CFTR channel activity and promoting proteasomal-mediated CFTR degradation. It is imperative to examine the effect of steviol in animal models of ADPKD.

Polycystin-1: a master regulator of intersecting cystic pathways.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal monogenic disorder, with more than 12 million cases worldwide. The two causative genes for ADPKD, PKD1 and PKD2, encode protein products polycystin-1 (PC1) and polycystin-2 (PC2 or TRPP2), respectively. Recent data have shed light on the role of PC1 in regulating the severity of the cystic phenotypes in ADPKD, autosomal recessive polycystic kidney disease (ARPKD), and isolated autosomal dominant polycystic liver disease (ADPLD).

Different effects of Sec61α, Sec62 and Sec63 depletion on transport of polypeptides into the endoplasmic reticulum of mammalian cells.

Co-translational transport of polypeptides into the endoplasmic reticulum (ER) involves the Sec61 channel and additional components such as the ER lumenal Hsp70 BiP and its membrane-resident co-chaperone Sec63p in yeast. We investigated whether silencing the SEC61A1 gene in human cells affects co- and post-translational transport of presecretory proteins into the ER and post-translational membrane integration of tail-anchored proteins. Although silencing the SEC61A1 gene in HeLa cells inhibited co- and post-translational transport of signal-peptide-containing precursor proteins into the ER of semi-permeabilized cells, silencing the SEC61A1 gene did not affect transport of various types of tail-anchored protein.

A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.

Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIβ and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIβ and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2.