ESPN 53rd Annual Meeting

ESPN 2021


 
High phosphate intake in mice causes inflammatory kidney injury dominated by macrophages
ISABEL VOGT 1 STEFANIE WALTER 1 TAMAR KAPANADZE 2 JESSICA SCHMITZ 3 JAN HINRICH BRAESEN 3 ROLAND SCHMITT 2 FLORIAN P. LIMBOURG 2 DIETER HAFFNER 1 BEATRICE RICHTER 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:

Dietary phosphate intake greatly exceeds the recommended daily allowance in the Western population. Epidemiologic studies link elevated phosphate levels with an increased cardiovascular and all-cause mortality, but the direct renal effects of chronic high dietary phosphate intake are still under investigation.

Material and methods:

Male C57BL/6 mice were fed with a 2 % high phosphate diet (HPD) or a 0.8 % normal phosphate diet (NPD) for up to six months. Blood, urine and kidneys were collected to investigate phosphate metabolism and kidney function, tissue alterations and inflammation. In vitro, we distinguish whether renal toxicity was directly mediated by phosphate or its phosphaturic hormone fibroblast growth factor (FGF) 23 in murine proximal tubule cells (mPTs).

Results:

Feeding a HPD increased plasma intact FGF23 levels, phosphaturia, plasma creatinine and albuminuria compared to NPD. The HPD induced proximal tubular injury characterized by loss of proximal tubular cell polarity, flattened epithelia, lack of brush border membranes, increased proliferation, mononuclear interstitial infiltration and finally fibrosis. HPD-fed mice showed renal upregulation of tubular injury marker Kim-1 and Ngal compared to NPD mice. Immunofluorescent staining revealed KIM-1 localization to damaged proximal tubules accompanied by enhanced Ki-67+ tubular nuclei, suggesting increased proliferation. F4/80+ macrophages were localized around tubular lesions and dominated the inflammatory response to the HPD. Accumulation of macrophages was accompanied by increased renal expression of chemotaxis and growth factors for monocytes and macrophages Mcp-1, M-csf and Il34 in HPD mice. In mPTs, high phosphate and FGF23 enhanced proliferation and stimulated the expression of Kim-1 and Mcp-1.

Conclusions:

Chronic oral phosphate loading in mice impaires kidney function and causes a robust inflammatory response dominated by macrophages that is associated with proximal tubular injury and interstitial fibrosis. Our in vitro data indicate that high phosphate and FGF23 may contribute to an inflammatory driven kidney injury in phosphate loaded mice.