Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease
Jacob A. Torres, … , Michal Mrug, Thomas Weimbs
Jacob A. Torres, … , Michal Mrug, Thomas Weimbs
Published July 30, 2019
Citation Information: J Clin Invest. 2019;129(10):4506-4522. https://doi.org/10.1172/JCI128503.
View: Text | PDF
Research Article Nephrology

Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease

  • Text
  • PDF
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.

Authors

Jacob A. Torres, Mina Rezaei, Caroline Broderick, Louis Lin, Xiaofang Wang, Bernd Hoppe, Benjamin D. Cowley Jr., Vincenzo Savica, Vicente E. Torres, Saeed Khan, Ross P. Holmes, Michal Mrug, Thomas Weimbs

×

Figure 4

mTOR inhibition blunts tubule dilation and hypertrophy after NaOx challenge and disrupts efficient CaOx crystal excretion.

Options: View larger image (or click on image) Download as PowerPoint
mTOR inhibition blunts tubule dilation and hypertrophy after NaOx challe...
(A) Immunoblots of kidney lysates. (B) Immunostaining 6 hours after treatment with NaOx, with or without rapamycin pretreatment. (C) Quantification of Ki67+ cells as a percentage of total cells. (D) Images showing immunostaining for the segment-specific markers AQP1 and AQP2. (E) Quantification of tubular and lumen diameters with rapamycin (+R). (F) Inverted polarized light micrographs of whole kidneys 6 hours or 3 days after NaOx treatment. (G) High-magnification polarized light micrographs showing oxalate crystals in renal cortex and the CMB 6 hours following NaOx treatment, with or without rapamycin pretreatment. (H) Pizzolato staining together with segment-specific markers in rapamycin-treated rats. Arrowheads point to crystals. CD, collecting duct; PT, proximal tubule. (I) Quantification of intrarenal location of deposited CaOx crystals 6 hours and 3 days after NaOx treatment, with and without rapamycin. (J) Quantification of the size distribution of CaOx crystals and aggregates in rats treated with NaOx, with or without rapamycin. NaOx-treated animals after 6 hours (n = 5), 1 day (n = 5), 3 days (n = 5), and 7 days (n = 3). NaOx- plus rapamycin-treated animals after 6 hours (n = 5), 1 day (n = 5), 3 days (n = 5), and 7 days (n = 2). Scale bars: 50 μm. Original magnification, ×3 (insets in G). Error bars represent the SD. All data are representative of 3 experiments for NaOx-treated animals. Box-and-whisker plots represent 90% of the values, with the median displayed as a line in between the second and third quartiles and the mean with intersecting bars. *P < 0.05, **P < 0.01, ***P < 0.001, and ψP < 0.0001, by Mann-Whitney U test.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts