Xiaoyan Wen Critical Care Medicine, Medicine, Center for Critical Care Nephrology P53 Mediates Acute Kidney Injury in Sepsis

Novel biomarkers for AKI early diagnosis Sepsis associated Acute Kidney Injury is a serious complication with high mortality Identifying early markers of kidney damage has been difficult Two novel urine markers have been identified for AKI prediction – Tissue inhibitor of metalloproteinases-2 (TIMP-2) – Insulin-Like Growth Factor Binding Protein 7 (IGFBP7) The underline mechanism is unclear – Speculated play roles in G1 cell cycle arrest

P53 induce cellular growth arrest in response to stresses p53 tumor suppressor protein is one of the potent adaptive genes in the cellular response to stress p53 was reported play critical roles in both ischemic and nephrotoxic AKI P53 can hold the cell cycle at the G1/S or G2/M regulation points, induce growth arrest or lead to apoptosis.

Hypothesis & Study methods Hypothesis: P53 play critical roles in sepsis associated AKI Strategy:  Apply p53 modulators  Measure cell cycle  Flow-up outcomes  Check associates between p53 activation and renal TIMP2, IGFBP7 expressions

P53 was modulated upon treatments

P53 modulators affect epithelial cells G0G1 and G2M growth arrest in the kidney

P53 modulators affect leukocytes G0G1 and G2M growth arrest in the kidneys

P53 modulators affect leukocyte profile

P53 activity mediates kidney dysfunction

TIMP2 was secreted in the kidneys during sepsis * Sham CLP 48 hours post CLP

P53 modulators affect TIMP2 secretion CLP CLP + UCN CLP + Pifi TIMP2DAPI

P53 modulators affect TIMP2.IGFBP7 secretion TIMP2 IGFBP7 DAPI TIMP2 IGFBP7 DAPI Sham UCN CLP Pifi

Anti-TIMP2 treatments had no effects on kidney function

Anti-IGFBP7 treatments had no effects on kidney function

Conclusion  P53 induce cell cycle arrest of both renal tubular epithelial cells and leukocytes during sepsis  P53 induced renal tubular epithelial cells’ growth arrest is one of the vital mechanisms leading to acute kidney injury in sepsis  Tubular cells secreted TIMP2 and IGFBP7 are the downstream signals of p53 activation, and could be used as one of the auxiliary diagnostic tools for acute kidney injury in sepsis patients.

Acknowledgement John A. Kellum MD Visiting fellows Jicheng Zhang, MD PhD Xiaojian Wan, MD PhD Xin Qu, MD PhD Liyan Cui, MD PhD Center for Critical Care Nephrology (CCCN) CRISMA David Emlet, PhD Jacob Volpe  Pittsburgh Institute For Neurodegenerative Diseases (PIND)  Thomas E. Starzl Transplantaion Institute (STI) Flow Core  Center for Biological Imaging (CBI), Department of Physiology and Cell Biology  Astute Medical Inc.

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