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


ABSTRACT: The rate of disease progression in autosomal-dominant (AD) polycystic kidney disease (PKD) exhibits high intra-familial 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 previously been recognized. Challenging PKD rat models with CaOx crystal deposition, or inducing calcium phosphate deposition by increasing dietary phosphorous intake, led to increased cystogenesis and disease progression. In a cohort of ADPKD patients, lower levels of urinary excretion of citrate, an endogenous inhibitor of calcium crystal formation, correlated with increased disease severity. These results suggest that PKD progression may be accelerated by commonly occurring renal crystal deposition which could be therapeutically controlled by relatively simple measures.

SUBMITTER: Torres JA 

PROVIDER: S-EPMC6763267 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Torres Jacob A JA   Rezaei Mina M   Broderick Caroline C   Lin Louis L   Wang Xiaofang X   Hoppe Bernd B   Cowley Benjamin D BD   Savica Vincenzo V   Torres Vicente E VE   Khan Saeed S   Holmes Ross P RP   Mrug Michal M   Weimbs Thomas T  

The Journal of clinical investigation 20190730 10


The rate of disease progression in autosomal-dominant (AD) polycystic kidney disease (PKD) exhibits high intra-familial 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  ...[more]

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