THE EFFECTS OF HYPOXIA-INDUCIBLE FACTOR-2 INACTIVATION IN MURINE KIDNEY DISEASE MODELS

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https://storage.unitedwebnetwork.com/files/1099/eea05cde1c25dd0ce48e85d719af657f.pdf

Abstract Title

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PEI-ZHEN

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TSAI

Co-author 1

Szu-Yu Pan gpsforeveryoung@gmail.com National Taiwan University Hospital Renal Division, Department of Internal Medicine Taipei

Co-author 2

Shuei-Liong Lin linsl@ntu.edu.tw National Taiwan University College of Medicine Graduate Institute of Physiology Taipei

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Introduction

Inhibition of hypoxia-inducible factor-2 (HIF-2) is a promising therapeutic approach in Von Hippel–Lindau syndrome and renal cell carcinoma. However, the effects of HIF-2 inhibition on renal function in patients with kidney disease are unclear. We aim to study the effects of HIF-2 inactivation in preclinical kidney injury models.

Methods

Tg(UBC-CreERT2);Epas1F/F mice were used to achieve global inactivation of HIF-2 through tamoxifen induction. Three different kidney injury models, unilateral ischemia-reperfusion injury and contralateral nephrectomy (uIRIx), adenine nephropathy, and unilateral ureteral obstruction (UUO), were used to characterize kidney injury. Blood urea nitrogen and serum creatinine levels were used to estimate renal function. In the kidney, the severity of injury was measured by the mRNA level of Havcr1, encoding kidney injury molecule-1 (KIM-1). Kidney inflammation was estimated by the mRNA levels of Ptprc (encoding CD45) and Adgre1 (encoding F4/80). Kidney fibrosis was assessed by the mRNA levels of Col1a1 and Acta2 (encoding α-smooth muscle actin, α-SMA).

Results

Compared with littermate Epas1F/F mice, Tg(UBC-CreERT2);Epas1F/F mice had remarkably decreased hematocrit in all the three kidney injury models, indicating successful inactivation of HIF-2 in these models. However, there were no consistent changes in kidney injury after HIF-2 inactivation in these models. The levels of blood urea nitrogen and serum creatinine were statistically indifferent between Epas1F/F and Tg(UBC-CreERT2);Epas1F/F mice in all three models. In the uIRIx model, no changes in mRNA levels of Havcr1, Ptprc, Adgre1, Col1a1, or Acta2 could be observed in mice harboring global Epas1 deletion. In the adenine nephropathy model, the levels of Havcr1, Ptprc, and Acta2 did not have significant changes, while the levels of Adgre1 and Col1a1 decreased in Tg(UBC-CreERT2);Epas1F/F mice. In the UUO model, although the levels of Havcr1 slightly decreased in Tg(UBC-CreERT2);Epas1F/F mice, no difference could be observed in the levels of Adgre1, Col1a1, Col3a1, or Acta2.

Conclusions

HIF-2 inactivation does not have remarkable impacts on kidney injury in preclinical models.

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