Mechanisms of renal injury during high phosphate loading

• Applicant: Dr. Beatrice Richter
• Subject Area: Nephrology ; Pediatric and Adolescent Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 516331703

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.

• DFG Programme: Research Grants