University of California Santa Barbara, Department of Molecular, Cellular, and Developmental Biology, and Neuroscience Research Institute, Santa Barbara, California, USA.
Mayo Clinic College of Medicine, Division of Nephrology and Hypertension, Rochester, Minnesota, USA.
J Clin Invest. 2019 Jul 30;129(10):4506-4522. doi: 10.1172/JCI128503.
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.
常染色体显性遗传多囊肾病 (ADPKD) 的疾病进展速度在家族内具有高度变异性，这表明环境因素可能起作用。我们假设普遍存在的肾脏损伤形式可能会加速囊性进展，并研究了管状晶体沉积。我们报告称，草酸钙 (CaOx) 晶体沉积导致肾小管迅速扩张，激活与 PKD 相关的信号通路，并导致受影响的肾单位中的肾小管段肥大。阻断 mTOR 信号通路会减弱这种反应，并抑制嵌入晶体的有效排泄。这种通过有目的地扩张肾小管来“冲出”晶体的机制以前尚未被认识到。用 CaOx 晶体沉积挑战 PKD 大鼠模型，或通过增加饮食磷摄入来诱导磷酸钙沉积，会导致囊肿形成和疾病进展增加。在一组 ADPKD 患者中，尿中柠檬酸排泄减少，柠檬酸是一种内源性钙晶体形成抑制剂，与疾病严重程度增加相关。这些结果表明，常见的肾脏晶体沉积可能会加速 PKD 的进展，而通过相对简单的措施可以对其进行治疗控制。
