ESPN 54th Annual Meeting

ESPN 2022


 
High phosphate load-induced proximal tubular injury is associated with activated Stat3/Kim-1 signaling and macrophage recruitment
BEATRICE RICHTER 1 TAMAR KAPANADZE 2 NINA WEINGäRTNER 1 STEFANIE WALTER 1 ISABEL VOGT 1 ANDREA GRUND 1 JESSICA SCHMITZ 3 JAN HINRICH BRäSEN 3 FLORIAN P. LIMBOURG 2 DIETER HAFFNER 1 MAREN LEIFHEIT-NESTLER 1

1- DEPARTMENT OF PEDIATRIC KIDNEY, LIVER AND METABOLIC DISEASES, PEDIATRIC RESEARCH CENTER, HANNOVER MEDICAL SCHOOL, HANNOVER, GERMANY
2- DEPARTMENT OF NEPHROLOGY AND HYPERTENSION, HANNOVER MEDICAL SCHOOL, HANNOVER, GERMANY
3- INSTITUTE OF PATHOLOGY, NEPHROPATHOLOGY UNIT, HANNOVER MEDICAL SCHOOL, HANNOVER, GERMANY
 
Introduction:

High phosphate is linked to enhanced all-cause mortality and responsible for the progression of kidney damage in patients with chronic kidney disease. However, it is unclear whether a high phosphate diet (HPD) causes kidney injury in healthy individuals.

Material and methods:

C57BL/6N mice were either fed with a 2% HPD or a 0.8% normal phosphate diet (NPD) for one up to six months and investigated for parameters of phosphate homeostasis and development of kidney injury. The specific impact of phosphate and its phosphaturic hormones fibroblast growth factor (FGF) 23 and parathyroid hormone (PTH) on tubular cell damage was investigated using HK-2 human proximal tubular (PT) cells.

Results:

HPD in mice caused hyperphosphatemia, hyperphosphaturia, increased FGF23, PTH and creatinine levels and albuminuria. Histopathological analysis revealed progressive PT injury in HPD-fed mice from two months onwards followed by a rapid progression from month 5 to 6. This was accompanied by increased tubulointerstitial fibrosis. The kidney injury marker Kim-1 increased in PT of HPD-fed mice, which was positively associated with tubular injury score and tubulointerstitial fibrosis. Histological staining revealed increased number of pStat3+ cells that was positively associated with Kim-1 synthesis. Concomittantly, the chemokine MCP-1 was upregulated in PT of HPD-fed mice, which was associated with Kim-1 expression indicating an interaction between pStat3/Kim-1 signaling and MCP-1. HPD caused enhanced macrophage recruitment to injured PT that was associated with increased MCP-1 synthesis and increased tubular injury score. Stimulation of HK-2 cells with FGF23 or high phosphate, but not PTH, induced the phosphorylation of Stat3. Interestingly, only high phosphate significantly upregulated Kim-1 and MCP-1 expression.

Conclusions:

Chronic high phosphate load leads to progressive PT damage caused by Stat3/Kim-1 signaling activation mediating MCP-1-dependent macrophage recruitment. Our data indicate that high phosphate intake may cause a global health problem and the demand for clinical studies on this issue.