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 language | English (US) |
|---|---|
| Pages (from-to) | 4506-4522 |
| Number of pages | 17 |
| Journal | Journal of Clinical Investigation |
| Volume | 129 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 1 2019 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease
AU - Torres, Jacob A.
AU - Rezaei, Mina
AU - Broderick, Caroline
AU - Lin, Louis
AU - Wang, Xiaofang
AU - Hoppe, Bernd
AU - Cowley, Benjamin D.
AU - Savica, Vincenzo
AU - Torres, Vicente E.
AU - Khan, Saeed
AU - Holmes, Ross P.
AU - Mrug, Michal
AU - Weimbs, Thomas
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070832495&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070832495&partnerID=8YFLogxK
U2 - 10.1172/JCI128503
DO - 10.1172/JCI128503
M3 - Article
C2 - 31361604
AN - SCOPUS:85070832495
VL - 129
SP - 4506
EP - 4522
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 10
ER -