@article{751fbd7081ed4865a6f15a9ce5a622fe,
title = "Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease",
abstract = "The rate of disease progression in autosomal-dominant polycystic kidney disease (ADPKD) has high intrafamilial variability, suggesting that environmental factors may play a role. We hypothesized that a prevalent form of renal insult may accelerate cystic progression and investigated tubular crystal deposition. We report that calcium oxalate (CaOx) crystal deposition led to rapid tubule dilation, activation of PKD-associated signaling pathways, and hypertrophy in tubule segments along the affected nephrons. Blocking mTOR signaling blunted this response and inhibited efficient excretion of lodged crystals. This mechanism of {"}flushing out{"} crystals by purposefully dilating renal tubules has not to our knowledge been previously recognized. Challenging PKD rat models with CaOx crystal deposition or inducing calcium phosphate deposition by increasing dietary phosphorus intake led to increased cystogenesis and disease progression. In a cohort of patients with ADPKD, lower levels of urinary excretion of citrate, an endogenous inhibitor of calcium crystal formation, were correlated with increased disease severity. These results suggest that PKD progression may be accelerated by commonly occurring renal crystal deposition that could be therapeutically controlled by relatively simple measures.",
author = "Torres, {Jacob A.} and Mina Rezaei and Caroline Broderick and Louis Lin and Xiaofang Wang and Bernd Hoppe and Cowley, {Benjamin D.} and Vincenzo Savica and Torres, {Vicente E.} and Saeed Khan and Holmes, {Ross P.} and Michal Mrug and Thomas Weimbs",
note = "Funding Information: Authorship note: JAT and MR are co–first authors and contributed equally to this work. Conflict of interest: JT and TW are listed inventors on a provisional patent application (62818538) by the University of California Santa Barbara (UCSB) related to discoveries reported in this paper. TW is an inventor on a patent application (15/326296) by UCSB. BC reports consulting fees from Otsuka Pharmaceuticals. MM reports grants and consulting fees from Otsuka Pharmaceuticals, Sanofi, and Chinook Therapeutics. BH is a consultant for Oxthera AB, Alexion Pharmaceuticals, Dicerna Pharmaceuticals, Alnylam Pharmaceuticals, and Allena Pharmaceuticals. RH is on the Advisory Board of Chinook Therapeutics and is an inventor on 2 pending patents (15/545818 and 62/849564) filed by Wake Forest University and UAB. VET reports grant funding from Otsuka Pharmaceuticals, Palladio Biosciences, Sanofi Genzyme, Acceleron Pharma Inc., Regulus Therapeutics, and Blueprint Medicines. Copyright: {\textcopyright} 2019, American Society for Clinical Investigation. Submitted: March 1, 2019; Accepted: July 23, 2019; Published: September 16, 2019. Reference information: J Clin Invest. 2019;129(10):4506–4522. https://doi.org/10.1172/JCI128503. Funding Information: We thank Arlene Chapman (University of Chicago) for providing patients{\textquoteright} urine samples. This work was supported by a grant from the NIH (DK109563) and gifts from the Lillian Goldman Charitable Trust and the Amy P. Goldman Foundation (to TW); a Jarrett Postdoctoral Fellowship from the Jarrett Family Fund for work in TW{\textquoteright}s laboratory; grants from the NIH (DK44863 and DK90728); the Mayo Clinic Robert M. and Billie Kelley Pirnie Translational PKD Research Center (to VET); a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (to VET); an Early Postdoctoral Mobility Grant (P2BEP3-152098); and an Advanced Postdoctoral Mobility Grant (P300PB_167797) from the Swiss National Science Foundation (to MR). MM was supported in part by grants from the NIH (UAB Hepato/Renal Fibrocystic Disease Core Center, P30 DK074038 and DK097423) and the Office of Research and Development, Medical Research Service, Department of Veterans Affairs (1-I01-BX002298). Additional support was provided by the NIH-funded UAB-UCSD O{\textquoteright}Brien Center (1P30 DK079337). The mass spectrometer used in these studies was obtained through a grant from the UAB Health Services Foundation General Endowment Fund. Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",
year = "2019",
month = oct,
day = "1",
doi = "10.1172/JCI128503",
language = "English (US)",
volume = "129",
pages = "4506--4522",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",
}