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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. Approximately one quarter of families with ADPDK due to Pkd1 have germline nonsynonymous amino acid substitution (missense) mutations. A subset of these mutations is hypomorphic, retaining some residual PC1 function. Previous studies have shown that the highly conserved Ire1 α -XBP1 pathway of the unfolded protein response can modulate levels of functional PC1 in the presence of mutations in genes required for post-translational maturation of integral membrane proteins. We examine how activity of the endoplasmic reticulum chaperone-inducing transcription factor XBP1 affects ADPKD in a murine model with missense Pkd1 ., Methods: We engineered a Pkd1 REJ domain missense murine model, Pkd1 R2216W , on the basis of the orthologous human hypomorphic allele Pkd1 R2220W , and examined the effects of transgenic activation of XBP1 on ADPKD progression., Results: Expression of active XBP1 in cultured cells bearing PC1 R2216W mutations increased levels and ciliary trafficking of PC1 R2216W . Mice homozygous for Pkd1 R2216W or heterozygous for Pkd1 R2216Win trans with a conditional Pkd1 fl allele exhibit severe ADPKD following inactivation in neonates or adults. Transgenic expression of spliced XBP1 in tubule segments destined to form cysts reduced cell proliferation and improved Pkd progression, according to structural and functional parameters., Conclusions: Modulating ER chaperone function through XBP1 activity improved Pkd in a murine model of PC1, suggesting therapeutic targeting of hypomorphic mutations., (Copyright © 2022 by the American Society of Nephrology.)

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. Although significant regulatory progress has been made, with qualification of total kidney volume as a prognostic enrichment biomarker and its later designation as a reasonably likely surrogate endpoint for progression of ADPKD within clinical trials, further work is needed to accelerate drug development efforts for all forms of PKD. In May 2021, the PKD Outcomes Consortium at the Critical Path Institute and the PKD Foundation organized a PKD Regulatory Summit to spur conversations among patients, industry, academic, and regulatory stakeholders regarding future development of tools and drugs for ADPKD and autosomal recessive polycystic kidney disease. This Special Report reviews the key points discussed during the summit and provides future direction related to PKD drug development tools., (© 2022 The Authors.)

Approximately 15% of autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in PKD2 PKD2 encodes polycystin-2, which forms an ion channel in primary cilia and endoplasmic reticulum (ER) membranes of renal collecting duct cells. Elevated internal Ca 2+ 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 2+ occupancy of the polycystin-2 intracellular EF hand is responsible for these forms of channel regulation, and, if disrupted, results in ADPKD. We identify and introduce mutations that attenuate Ca 2+ -EF hand affinity but find channel function is unaltered in the primary cilia and ER membranes. We generated two new mouse strains that harbor distinct mutations that abolish Ca 2+ -EF hand association but do not result in a PKD phenotype. Our findings suggest that additional Ca 2+ -binding sites within polycystin-2 or Ca 2+ -dependent modifiers are responsible for regulating channel activity., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Background: SEC63 encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of Sec63 in all distal nephron segments in embryonic mouse kidney results in polycystin-1-mediated polycystic kidney disease (PKD). It also activates the Ire1 α -Xbp1 branch of the unfolded protein response, producing Xbp1s, the active transcription factor promoting expression of specific genes to alleviate endoplasmic reticulum stress. Simultaneous inactivation of Xbp1 and Sec63 worsens PKD in this model., Methods: We explored the renal effects of postnatal inactivation of Sec63 alone or with concomitant inactivation of Xbp1 or Ire1α , specifically in the collecting ducts of neonatal mice., Results: The later onset of inactivation of Sec63 restricted to the collecting duct does not result in overt activation of the Ire1 α -Xbp1 pathway or cause polycystin-1-dependent PKD. Inactivating Sec63 along with either Xbp1 or Ire1α in this model causes interstitial inflammation and associated fibrosis with decline in kidney function over several months. Re-expression of XBP1s in vivo completely rescues the chronic kidney injury observed after inactivation of Sec63 with either Xbp1 or Ire1α ., Conclusions: In the absence of Sec63 , basal levels of Xbp1s activity in collecting ducts is both necessary and sufficient to maintain proteostasis (protein homeostasis) and protect against inflammation, myofibroblast activation, and kidney functional decline. The Sec63-Xbp1 double knockout mouse offers a novel genetic model of chronic tubulointerstitial kidney injury, using collecting duct proteostasis defects as a platform for discovery of signals that may underlie CKD of disparate etiologies., (Copyright © 2019 by the American Society of Nephrology.)

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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. Furthermore, simultaneous podocyte-specific genetic inactivation of X-box binding protein-1 (Xbp1), a transcription factor activated during endoplasmic reticulum stress and critically involved in the untranslated protein response, and Sec63, a heat shock protein-40 chaperone required for protein folding in the endoplasmic reticulum, resulted in progressive albuminuria, foot process effacement, and histology consistent with ESRD. Finally, loss of both Sec63 and Xbp1 induced apoptosis in podocytes, which associated with activation of the JNK pathway. Collectively, our results indicate that an intact Xbp1 pathway operating to mitigate stress in the endoplasmic reticulum is essential for the maintenance of a normal glomerular filtration barrier., (Copyright © 2016 by the American Society of Nephrology.)

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. Here we show, using a combination of mass spectrometry and biochemical approaches, that native TRPP2 is glycosylated at five asparagines in the first extracellular loop. Glycosylation is required for the efficient biogenesis of TRPP2 because mutations of the glycosylated asparagines result in strongly decreased protein expression of the ion channel. Wild-type and N-glycosylation-deficient TRPP2 is degraded in lysosomes, as shown by increased TRPP2 protein levels upon chemical inhibition of lysosomal degradation. In addition, using pharmacological and genetic approaches, we demonstrate that glucosidase II (GII) mediates glycan trimming of TRPP2. The non-catalytic β subunit of glucosidase II (GIIβ) is encoded by PRKCSH, one of the genes causing autosomal dominant polycystic liver disease (ADPLD). The impaired GIIβ-dependent glucose trimming of TRPP2 glycosylation in ADPLD may explain the decreased TRPP2 protein expression in Prkcsh(-/-) mice and the genetic interaction observed between TRPP2 and PRKCSH in ADPLD. These results highlight the biological importance of N-linked glycosylation and GII-mediated glycan trimming in the control of biogenesis and stability of TRPP2., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Epithelial cell polarity is essential for organ development; aberrations in this process have been implicated in various diseases, including polycystic kidney disease. Establishment and maintenance of cell polarity is governed by a number of molecular processes and how these processes operate remains an interesting question. Conserved protein complexes guide both apical-basolateral polarity and planar cell polarity. In this review we discuss the recent findings that provide insights into polarity mechanisms and the intriguing crosstalk between apical-basolateral polarity and planar cell polarity, and their relationship to cystic kidney disease.