Abstract: TH-PO313

Lack of Vasohibin-1, a Negative Feedback Regulator of Angiogenesis, Exacerbates Renal Injury in a Murine Cisplatin Nephropathy Model

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Tanimura, Satoshi, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
  • Tanabe, Katsuyuki, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
  • Masuda, Kana, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
  • Miyake, Hiromasa, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
  • Sugiyama, Hitoshi, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
  • Wada, Jun, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Background

Vasohibin-1 (VASH1) was originally identified as an endothelium-derived anti-angiogenic factor. In contrast to other anti-angiogenic factors, VASH-1 has been shown to enhance stress-tolerance and survival of endothelial cells via upregulation of Sirt1 and SOD2. We previously reported that VASH1 deficiency resulted in the exacerbation of renal inflammation and interstitial fibrosis in murine unilateral obstruction model (Watatani et al., Phys Rep 2012), and increased albuminuria and marked glomerular alterations in murine type 1 diabetes model (Hinamoto et al., PLoS ONE 2014). In the present study, we examined the effect of VASH-1 deficiency on cisplatin-induced AKI.

Methods

Nine-week-old male VASH1+/- (C57BL/6 background) and wild type (WT) mice received once intraperitoneal injection of 20mg/kg of cisplatin or saline (vehicle). Mice were divided into four groups; 1) WT-control (n=5), 2) VASH1+/--control (n=5), 3) WT-cisplatin (n=7), and 4) VASH1+/--cisplatin (n=7). 72 hours after the injection, these mice were sacrificed and blood and kidney samples were collected.

Results

There were no differences in renal function and histology between WT and VASH1+/--control mice. Renal dysfunction induced by cisplatin injection was more prominent in VASH1+/--cisplatin compared with WT-cisplatin mice (serum creatinine 1.18 ± 0.52 vs 0.39 ± 0.11 mg/dl; BUN 140.9 ± 16.1 vs 92.4 ± 14.0 mg/dl, respectively). Increased renal tubular injury scores and number of TUNEL positive nuclei were also greater in VASH1+/--cisplatin mice. Furthermore, loss of peritubular capillaries observed in WT-cisplatin mice was exacerbated in VASH1+/--cisplatin mice. Renal accumulation of oxidative stress markers, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were markedly increased in VASH1+/--cisplatin mice compared with WT mice. Along with the results, decreased level of antioxidative enzyme SOD2 in WT-cicplatin mice was significantly accelerated in VASH1+/--cisplatin mice.

Conclusion

VASH1 deficiency exacerbated renal dysfunction and tubular injury as well as increased oxidative stress. SOD2 may influence the number of PTCs and renal function. These results suggest that VASH1 exerts renal protective effect in AKI through preserved peritubular capillaries and SOD2 expression.

Funding

  • Government Support - Non-U.S.