Mechanisms of renal injury during high phosphate loading

磷是一种天然存在的元素，对我们体内的正常细胞功能具有重要作用。加工食品消费量的增加增加了无机磷酸盐的膳食摄入量。不仅肾病患者的健康风险增加，而且可能是一般人群。在慢性肾脏疾病的进展过程中，当肾功能下降时，血清磷酸盐水平升高。流行病学研究表明，富含磷酸盐的饮食或血清磷酸盐水平升高与心血管和全因死亡率之间存在相关性。此外，高磷酸盐摄入量与2型糖尿病，骨骼健康受损和过早衰老有关。其背后的病理机制尚未完全了解。我们小组的新数据表明，在健康小鼠中，高磷酸盐饮食增加磷酸盐排泄，导致肾近端小管损伤，伴随免疫细胞积聚和组织纤维化的发展。在高磷酸盐饮食六个月后，小鼠显示肾功能下降。据推测，高磷酸盐负荷与肾脏中的炎症过程和炎症标志物增加有关。转录因子STAT 3（信号转导和转录激活因子3）在激活后易位到细胞核中，并在那里调节靶基因的表达。其中一个靶基因是MCP-1（巨噬细胞引诱蛋白1），它促进巨噬细胞的局部募集。本研究的假设是，在肾脏中，STAT 3介导磷酸盐诱导的巨噬细胞积聚和纤维化。我们将研究巨噬细胞的消耗是否可以减少高磷饮食后肾损伤的进展。在STAT 3方面，我们将研究在高磷酸盐负荷的STAT 3敲除小鼠模型中，肾小管损伤、肾纤维化和巨噬细胞积聚是否受到抑制。此外，我们将研究是否可以通过使高磷酸盐负荷正常化在早期阶段阻止或预防肾损伤的进展。更详细地说，将在细胞培养实验中使用人近端小管上皮细胞和与巨噬细胞共培养物研究分子机制。如果成功的话，我们的研究结果可以作为可能的预防和治疗干预的基础，以治疗肾脏疾病。

Phosphorus is a naturally occurring element with essential functions for the normal cell function in our body. The enhanced consumption of processed food increases the dietary intake of inorganic phosphate. Not only patients with kidney disease have an increased health risk, but also possibly the general population. During the progression of chronic kidney disease, the serum phosphate levels rise when the kidney function declines. Epidemiologic studies show a correlation between a phosphate-rich diet or elevated serum phosphate levels and cardiovascular and all-cause mortality. Furthermore, a high phosphate intake is related to type 2 diabetes, impaired bone health and premature aging. The patho mechanisms behind are still not fully understand. New data of our group show that in healthy mice a high phosphate diet increases the phosphate excretion and causes an injury of renal proximal tubule coupled with an accumulation of immune cells and development of tissue fibrosis. After six months on high phosphate diet, mice display reduced kidney function. It is assumed that high phosphate load is associated with inflammatory processes in the kidney and increased markers of inflammation. The transcription factor STAT3 (signal transducers and activators of transcription 3) translocates into the cell nuclei after activation and there, it modulates the expression of target genes. One of the target genes is MCP-1 (macrophage attractant protein 1), which promotes the local recruitment of macrophages. The hypothesis of this study is that in the kidney STAT3 is mediating the phosphate-induced macrophage accumulation and fibrosis. We will investigate, if the depletion of macrophages can reduce the progression of renal injury after high phosphate diet. In terms of STAT3, we will study, if the tubular damage, renal fibrosis and macrophage accumulation is suppressed in a STAT3 knockout mouse model on high phosphate load. Furthermore, we will investigate, if the progression of renal injury can be stopped or prevented in early stages by normalizing high phosphate load. For more detail, the molecular mechanisms will be studied in cell culture experiments using human epithelial cell of the proximal tubule and co-cultures with macrophages. If successful, our results could serve as the base for possible prevention and therapeutic intervention to treat renal diseases.