Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
Yurina Medical Park, Shimotsuga, Japan.
J Clin Invest. 2021 Aug 16;131(16). doi: 10.1172/JCI145693.
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.
西方饮食模式不仅富含脂肪和卡路里，还富含磷酸盐。人们广泛认识到过量摄入脂肪和卡路里对健康的负面影响，但对过量摄入磷酸盐的潜在危害认识不足。在这里，我们展示了饮食磷酸盐损害肾脏的机制。当磷酸盐的摄入量相对于有功能的肾单位数量过多时，循环中的 FGF23（一种增加每个肾单位磷酸盐排泄的激素）水平会升高，以维持磷酸盐的体内平衡。FGF23 抑制了肾小管中的磷酸盐重吸收，从而提高了肾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就会出现在肾小管腔中，通过与它们表达的 TLR4 结合而损伤肾小管细胞。持续的肾小管损伤诱导间质纤维化，减少了肾单位的数量，并进一步促进 FGF23 的产生，引发恶化螺旋，导致进行性肾单位损失。在人类中，当血清 FGF23 水平超过 53pg/mL 时，慢性肾脏病（CKD）就会进展。本研究鉴定出肾管状液中的磷酸钙颗粒是一种有效的治疗靶点，可以在衰老和 CKD 进展过程中减缓肾单位的损失。
