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It is unclear whether a chronic high phosphate diet (HPD) causes kidney injury in healthy individuals. Here, we show that feeding a 2% HPD in C57BL\/6N mice for one up to six months resulted in hyperphosphatemia, hyperphosphaturia, increased plasma levels of fibroblast growth factor (FGF) 23, and parathyroid hormone (PTH) compared to mice on a 0.8% phosphate diet. Kidney injury was already noted after two months of HPD characterized by loss of proximal tubular (PT) cell polarity, flattened epithelia, disruption of brush border membranes, vacuolization, increased PT cell proliferation, marked interstitial mononuclear infiltration, and progressive accumulation of collagen fibers. HPD increased Stat3 activation and Kim\u20101 expression in PT epithelial cells and enhanced renal synthesis of chemokines recruiting monocytes and macrophages as well as macrophage related factors. Enhanced recruitment of F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    macrophages around injured PT lesions was timely associated with increased Kim\u20101 synthesis, tubular MCP\u20101 expression, and degree of PT injury score. Likewise, tubulointerstitial fibrosis was associated with activation of Stat3\/Kim\u20101 signaling pathway. The stimulation of human proximal tubular cells with high phosphate activated Stat3 signaling and induced\n                    <jats:italic>HAVCR1<\/jats:italic>\n                    and\n                    <jats:italic>CCL2<\/jats:italic>\n                    expression. We conclude that high phosphate results in progressive proximal tubular injury, indicating that high dietary phosphate intake may affect kidney health and therefore represents an underestimated health problem for the general population.\n                  <\/jats:p>","DOI":"10.1096\/fj.202200167rr","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T10:04:57Z","timestamp":1655460297000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["High phosphate\u2010induced progressive proximal tubular injury is associated with the activation of Stat3\/Kim\u20101 signaling pathway and macrophage recruitment"],"prefix":"10.1096","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3550-8571","authenticated-orcid":false,"given":"Beatrice","family":"Richter","sequence":"first","affiliation":[{"name":"Department of Pediatric Kidney, Liver and Metabolic Diseases, Pediatric Research 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