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

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4506-4522
Number of pages17
JournalJournal of Clinical Investigation
Volume129
Issue number10
DOIs
StatePublished - Oct 1 2019

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Polycystic Kidney Diseases
Autosomal Dominant Polycystic Kidney
Dilatation
Calcium Oxalate
Kidney
Disease Progression
Dietary Phosphorus
Nephrons
Citric Acid
Hypertrophy
Calcium

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Torres, J. A., Rezaei, M., Broderick, C., Lin, L., Wang, X., Hoppe, B., ... Weimbs, T. (2019). Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease. Journal of Clinical Investigation, 129(10), 4506-4522. https://doi.org/10.1172/JCI128503

Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease. / Torres, Jacob A.; Rezaei, Mina; Broderick, Caroline; Lin, Louis; Wang, Xiaofang; Hoppe, Bernd; Cowley, Benjamin D.; Savica, Vincenzo; Torres, Vicente E.; Khan, Saeed; Holmes, Ross P.; Mrug, Michal; Weimbs, Thomas.

In: Journal of Clinical Investigation, Vol. 129, No. 10, 01.10.2019, p. 4506-4522.

Research output: Contribution to journalArticle

Torres, JA, Rezaei, M, Broderick, C, Lin, L, Wang, X, Hoppe, B, Cowley, BD, Savica, V, Torres, VE, Khan, S, Holmes, RP, Mrug, M & Weimbs, T 2019, 'Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease', Journal of Clinical Investigation, vol. 129, no. 10, pp. 4506-4522. https://doi.org/10.1172/JCI128503
Torres, Jacob A. ; Rezaei, Mina ; Broderick, Caroline ; Lin, Louis ; Wang, Xiaofang ; Hoppe, Bernd ; Cowley, Benjamin D. ; Savica, Vincenzo ; Torres, Vicente E. ; Khan, Saeed ; Holmes, Ross P. ; Mrug, Michal ; Weimbs, Thomas. / Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 10. pp. 4506-4522.
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