High phosphate‐induced progressive proximal tubular injury is associated with the activation of Stat3/Kim‐1 signaling pathway and macrophage recruitment

Abstract

Dietary phosphate intake in the Western population greatly exceeds the recommended dietary allowance and is linked to enhanced cardiovascular and all‐cause mortality. 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‐1 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+ macrophages around injured PT lesions was timely associated with increased Kim‐1 synthesis, tubular MCP‐1 expression, and degree of PT injury score. Likewise, tubulointerstitial fibrosis was associated with activation of Stat3/Kim‐1 signaling pathway. The stimulation of human proximal tubular cells with high phosphate activated Stat3 signaling and induced HAVCR1 and CCL2 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.

Possible contribution of phosphate to the pathogenesis of chronic kidney disease in dolphins

“…In this regard, Fujimura et al 24 reported that phosphate-induced mitochondrial damage in human proximal tubular cells was suppressed by the appropriate function of autophagy. Recent studies in human proximal tubular HK-2 cells have shown that phosphate is involved in cell damage by activating multiple intracellular signaling pathways 13 , 25 , 26 . Further detailed studies are required to determine if similar molecular mechanisms are involved in dolphin tubular cell injury.…”

The exacerbated hypokalemia in membranous glomerulonephritis due to proximal tubular injury: a neglect issue from a case report and literature review

“…However, the development of proximal tubular damage and the clinical course of membranous GN was not elucidated [ 4 ]. Furthermore, the development of proximal vacuolization might be the early manifestation of tubular injury [ 5 , 6 ]. The proximal tubular injury might be the early manifestation of further tubulointerstitial fibrosis.…”

Possible contribution of phosphate to the pathogenesis of chronic kidney disease in dolphins

“…In this regard, Fujimura et al 24 reported that phosphate-induced mitochondrial damage in human proximal tubular cells was suppressed by appropriate function of autophagy. Recent studies in human proximal tubular HK-2 cells have shown that phosphate is involved in cell damage by activating multiple intracellular signaling pathways 14,25,26 . Further detailed studies are required to determine if similar molecular mechanisms are involved in dolphin tubular cell injury.…”