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Abstract: SA-PO127

Soluble fms-Like Tyrosine Kinase-1 Promotes AKI and CKD After Renal Ischemia-Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Tsushima, Hideo, Nara Medical University, Kasihara-city, Japan
  • Eriguchi, Masahiro, Nara Medical University, Kasihara-city, Japan
  • Matsui, Masaru, Nara Prefecture General Medical Center, Nara, NARA, Japan
  • Kosugi, Takaaki, Nara Medical University, Kasihara-city, Japan
  • Nishimoto, Masatoshi, Nara Medical University, Kasihara-city, Japan
  • Tanabe, Kaori, Nara Medical University, Kasihara-city, Japan
  • Tagawa, Miho, Nara Medical University, Kasihara-city, Japan
  • Samejima, Ken-ichi, Nara Medical University, Kasihara-city, Japan
  • Tsuruya, Kazuhiko, Nara Medical University, Kasihara-city, Japan
Background

Soluble fms-like tyrosine kinase-1 (sFlt-1), which is extracellular domains of Flt-1, acts as an antagonist of both placental growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A). We previously reported that kidney is a main source of circulating sFlt-1 (about 50%). Generally, VEGF signaling is associated with angiogenesis and macrophage migration. Angiogenesis has a protective effect against renal ischemia, however macrophage migration contributes renal injury. The objective of this study is to examine the role of sFlt-1 in acute and chronic kidney injury after renal ischemia.

Methods

Unilateral or bilateral 30-minute renal ischemia were performed using sFlt-1 knockout (KO) and wild-type (WT) mice. For evaluation of acute kidney injury (AKI), plasma urea nitrogen levels and macrophage infiltration in the kidney were measured on day 1 and 7 after bilateral renal ischemia. Kidneys two weeks after unilateral renal ischemia were used for chronic kidney disease (CKD) model. Ischemic/non-ischemic kidney weight ratios (ischemic kidney weight divided by non-ischemic kidney weight) and renal fibrosis of the unilateral ischemic kidneys (Sirius red staining) were examined.

Results

After bilateral renal ischemia, plasma urea nitrogen levels from sFlt-1 KO mice were significantly lower than those from WT mice (130.5 ± 5.0 vs 164.0 ± 10.2 mg/dL, p=0.009 on day 1; 56.2 ± 2.9 vs 76.3 ± 4.1 mg/dL, p=0.001 on day 7). However, there was no difference in macrophage infiltration in the kidneys between sFlt-1 KO and WT mice on day 1 (49 ± 8 vs 59 ± 5/field, p=0.30). Two weeks after unilateral renal ischemia, ischemic/non-ischemic kidney weight ratios from sFlt-1 KO mice were significantly larger than those from WT mice (76.5 ± 7.6 vs 60.4 ± 1.9%; P=0.046). Finally, renal fibrosis from sFlt-1 KO mice was significantly reduced by 21.0% compared to WT mice (p=0.032).

Conclusion

sFlt-1, which is mainly secreted from kidneys, promotes AKI and following CKD after renal ischemia-reperfusion injury in a paracrine manner.