Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression
Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression
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DOI：
10.1172/jci145693
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发表时间：
2021-08-16
影响因子：
15.9
通讯作者：
Kuro-O, Makoto
中科院分区：
文献类型：
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作者：
Shiizaki, Kazuhiro;Tsubouchi, Asako;Kuro-O, Makoto
西式饮食不仅富含脂肪和热量，而且还富含磷酸盐。过量脂肪和热量摄入对健康的负面影响是众所周知的，但过量磷酸盐摄入的潜在危害却认识不足。在这里，我们展示了膳食磷酸盐损害肾脏的机制。当磷酸盐摄入量相对于功能肾单位的数量过多时，FGF 23（一种增加每个肾单位磷酸盐排泄的激素）的循环水平增加，以维持磷酸盐稳态。FGF 23抑制肾小管中的磷酸盐重吸收，从而提高小管液中的磷酸盐浓度。一旦超过阈值，含有磷酸钙晶体的微观颗粒出现在小管腔中，通过与表达在其上的TLR 4结合来破坏小管细胞。持续性肾小管损伤诱导间质纤维化，减少肾单位的数量，并进一步增加FGF 23，以触发恶化螺旋，导致进行性肾单位损失。在人类中，当血清FGF 23水平超过53 pg/mL时，慢性肾脏疾病（CKD）的进展随之而来。本研究确定肾小管液中的磷酸钙颗粒是一种有效的治疗靶点，可以减缓衰老和CKD进展过程中的肾单位丢失。
The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.