PB0803 - The role of VWF-ADAMTS13 axis in cisplatin-induced acute kidney injury in mice

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

SS

Satoshi Senzaki

Clinical Fellow
Department of General Medicine/Nara Medical University
Kashiharashi, Nara, Japan

Co-Author(s)

AK

Ayaka Kakiwaki

Clinical Fellow
Department of General Medicine/Nara Medical University
Kashihara, Nara, Japan
AS

Akihiro Sawa

Clinical Fellow
Department of General Medicine/Nara Medical University
Kashihara, Nara, Japan
NN

Nobushiro Nishimura

Clinical Fellow
Department of General Medicine/Nara Medical University
Kashihara, Nara, Japan
RY

Ryo Yoneima

Assistant Professor
Department of General Medicine/Nara Medical University
Kashihara, Nara, Japan
HK

Hiromasa Kawashima

Assistant Professor
Department of General Medicine/Nara Medical University
Kashihara, Nara, Japan
SO

Shiro Ono

Associate Professor
Department of General Medicine/Nara Medical University
Kashihara, Nara, Japan
KY

Kiyomi Yoshimoto

Associate Professor
Department of General Medicine/Nara Medical University
Kashihara, Nara, Japan
AS

Asuka Sakata

Assistant Professor
Medicinal biology of thrombosis and hemostasis/Nara Medical University
Kashihara, Nara, Japan
KT

Kohei Tatsumi

Associate Professor
Advanced Medical Science of Thrombosis and Hemostasis/Nara Medical University
Kashihara, Nara, Japan
MS

Mitsuhiko Sugimoto

Specially Appointed Professor
Department of General Medicine/Nara Medical University
Kashihara, Nara, Japan
Midori Shima

Dean
Thrombosis and Hemostasis Research Center, Nara Medical University, Kashihara, Japan
Kashihara, Nara, Japan
KN

Kenji Nishio

Professor
Department of General Medicine/Nara Medical University
Kashihara, Nara, Japan

Background: Cisplatin (CDDP) is known as an effective anticancer agent. However, approximately 20% of CDDP-treated patients develop acute kidney injury (AKI), the mechanisms of which are assumed to direct injury of the kidney epithelial cells and subsequent inflammation and vascular endothelial injury.

Aims: We hypothesized that CDDP-induced AKI are exacerbated by the activation of VWF-platelet axis and ameliorated by VWF-cleaving enzyme, ADAMTS13.

Methods: After 6 hours fasting, CDDP were intraperitoneally administered to male wild-type (WT) and ADAMTS13-knockout (KO) mice (C57BL/6 background) at the dose of 20 mg/kg body weight. Five days after the administration, vital signs (blood pressure; BP, heart rate; HR) and renal blood flow were measured, then blood and kidney samples were collected. Blood cell counts and biochemical analysis were performed using the blood samples, and histological analysis and gene expression analysis by qPCR were conducted using the kidney samples.

Results: Significant decreases in body weight, renal blood flow, and the number of white blood cells, coupled with significant increases in serum levels of blood urea nitrogen (BUN) and creatinine (Cre) were observed after CDDP administration. No significant changes in BP and HR were observed. Notably, the increases of serum BUN and Cre in KO mice were significantly higher than those in WT mice（BUN; 110.7 vs 279.4 mg/dL, Cre; 0.61 vs 1.82 mg/dL, for WT and KO, respectively）. Furthermore, gene expression levels of AKI markers, such as KIM-1 and NGAL, were significantly upregulated by CDDP administration in KO mice more than those in WT mice.

Conclusion(s): We clarified that ADAMTS13 deficiency exacerbates CDDP-induced AKI in a mouse model. Modulation of plasma levels of ADAMTS13 (i.e. administration of recombinant ADAMTS13) may be a novel treatment option toward drug-induced AKI.