Mechanisms of renal injury during high phosphate loading

高磷负荷期间肾损伤的机制

• 批准号: 516331703
• 负责人: Dr. Beatrice Richter
• 金额: --
• 依托单位: Klinik für pädiatrische Nieren-, Leber- und Stoffwechselerkrankungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/516331703?language=en
• 关键词: Mechanisms; renal; injury; during; phosphate

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.

磷是一种天然存在的元素，具有人体正常细胞功能所必需的功能。加工食品消费的增加增加了膳食中无机磷的摄入量。不仅肾病患者的健康风险增加，普通人群也可能如此。在慢性肾脏疾病的发展过程中，当肾功能下降时，血清磷水平会上升。流行病学研究表明，富含磷酸盐的饮食或升高的血磷水平与心血管和各种原因的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。其背后的致病机制仍不完全清楚。本课题组的新数据显示，在健康小鼠中，高磷饮食增加了磷酸盐的排泄，导致肾近端小管损伤，并伴随着免疫细胞的聚集和组织纤维化的发展。在高磷饮食六个月后，小鼠表现出肾功能下降。据推测，高磷负荷与肾脏的炎症过程和炎症标志物增加有关。转录因子STAT3(信号转导和转录激活子3)被激活后转位到细胞核中，在那里，它调节靶基因的表达。其中一个靶基因是MCP-1(巨噬细胞吸引蛋白1)，它促进巨噬细胞的局部募集。本研究的假设是，在肾脏中，STAT3介导了磷酸盐诱导的巨噬细胞聚集和纤维化。我们将研究，在高磷饮食后，巨噬细胞的耗尽是否可以减少肾脏损伤的进展。在STAT3方面，我们将研究在高磷负荷的STAT3基因敲除小鼠模型中，肾小管损伤、肾纤维化和巨噬细胞聚集是否受到抑制。此外，我们还将研究，是否可以通过使高磷负荷正常化在早期阻止或预防肾损伤的进展。关于更多细节，分子机制将在使用人近端小管上皮细胞的细胞培养实验中进行研究，并与巨噬细胞共同培养。如果成功，我们的结果可以作为可能的预防和治疗干预治疗肾脏疾病的基础。