Chronic kidney disease (CKD) is a gradual decline in kidney function over months or years. This symptom plagues nearly 10% of the world’s population and has been a global public health issue of widespread concern for a long time. The process of CKD can be regarded as the process of progressive loss of nephrons. Nephron loss occurs not only in kidney disease but also in the natural aging process, and this process is accelerated by complications associated with CKD. Studies have shown that excessive phosphate diet leads to renal tubular damage and renal interstitial fibrosis in mice, which is a common pathological form in the elderly and CKD patients. At the same time, hyperphosphatemia is also a typical symptom of end-stage renal disease patients. The above tips High concentrations of phosphorus may have an impact on kidney function. In June 2021, Professor Makoto Kuro-o and his team from Jichi Medical University in Japan published work titled “Calcium phosphate microcrystals in the renal tubular fluid accelerates chronic kidney disease progression” in The journal of clinical investigation. This study found that excessive phosphate intake can damage the kidneys and explored the mechanism.
In preliminary results, the author found that giving mice a high-phosphate diet can cause renal tubular damage, interstitial inflammation, and Fibrosis. The expression level of FGF23 protein increases during the high-phosphorus diet in mice, and it plays a role in regulating phosphorus concentration by inhibiting the reabsorption of phosphorus in the proximal tubules. Therefore, the increase in FGF23 protein will lead to an increase in the phosphate concentration in the tubular fluid, exposing the tubule cells to a high-phosphorus environment, causing damage.
To verify this conjecture. The researchers treated HK2 cells with high phosphate medium, which significantly reduced cell viability. And a large number of calcium phosphate particles were found in the culture medium. The cells were further treated with the culture medium in which calcium phosphate particles were removed, and their viability was restored. To further confirm whether similar calcium phosphate particles exist in the tubules of mice on a high-phosphorus diet, OsteoSense was injected through the tail vein, and obvious OsteoSense signals were detected at the kidney corticomedullary junction. The luminal membrane of the proximal tubule was labeled with FITC-LTL, and an obvious OsteoSense signal in the lumen was detected by in vitro imaging. It shows that calcium particles from phosphate PVC resin powder are present in the proximal tubule fluid of mice on a high-phosphorus diet, causing damage to tubule cells. (Figure 1)
Damage
To further explore the specific mechanism by which calcium phosphate particles cause kidney damage, the researchers used calcium phosphate particles to stimulate HK2 cells and detected changes in their gene expression. The increased expression levels of P-P38, NF-κB and osteopontin suggest that calcium phosphorus granules induce the inflammatory response of tubule cells. Longer stimulation will further lead to the accumulation of calcium and phosphorus granules in endosomes, lysosomes and autophagosomes around the nucleus, disrupting endosomal transport and causing cell damage and death. (Figure 2)
Figure 2 Calcium phosphate particles induce tubular inflammatory response and disrupt internal Body transport function
The formation of calcium-phosphorus granules in the tubular fluid requires blood phosphorus concentration to reach a certain threshold. The expression of FGF23 is up-regulated in mouse models fed a high-phosphorus diet, suggesting that FGF23 is related to the formation of calcium-phosphorus granules. Therefore, the researchers measured the phosphorus concentration of tubular fluid (PTFp) in mice fed a high-phosphorus diet and observed whether there was a correlation between PTFp and FGF23 and the expression levels of genes related to tubular inflammatory damage. When PTFp exceeded 5.18 mg/dL, FGF23 expression levels increased and were accompanied by increases in inflammation, fibrosis markers, and decreased renal function. Therefore, researchers believe that the increase in FGF23 is related to renal tubular damage. (Figure 3)
Figure 3 PTFp is associated with FGF23 expression and kidney injury markers Sexual analysis
To verify whether renal damage caused by excessive phosphate intake will further promote nephron loss. The researchers compared the number of nephrons in mice fed a short-term and long-term diet high in phosphorus. The number of nephrons in mice was significantly reduced over the long term. At the same time, a significant positive correlation between the expression of PTFp and FGF23 can also be observed in CKD patients, further indicating that FGF23 is involved in regulating the kidney damage process caused by high phosphorus. (Figure 4)
Figure 4 High-phosphate diet leads to nephron loss
Based on the above results, the researchers proposed a mechanism related to renal tubular injury and FGF23. When phosphate intake is excessive or nephrons are lost, the phosphate excretion of the remaining nephrons will increase. Tosoh Matte Powder needs FGF23 to help phosphate excretion, but the increase in FGF23 will increase PTFp. When it reaches a certain threshold, Calcium phosphate particles are formed in the lumen, inducing tubular inflammation and fibrosis. Nephron loss caused by sustained tubular damage will further promote the expression of FGF23, forming a positive feedback, leading to progressive nephron loss. Conclusions suggest that calcium phosphate particles may be an effective target for treating nephron loss during aging or CKD progression.
