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Kidney Week

Abstract: TH-PO492

Dual Disruption of Endothelial Nitric Oxide Synthase and ApoE Gene Accelerates Kidney Fibrosis and Aging After Injury

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Nishimura, Kenji, Tokushima University Hospital, Tokushima, Japan
  • Kishi, Seiji, Tokushima University Hospital, Tokushima, Japan
  • Ochi, Arisa, Tokushima University Hospital, Tokushima, Japan
  • Ono, Hiroyuki, Tokushima University Hospital, Tokushima, Japan
  • Tamaki, Masanori, Tokushima University Hospital, Tokushima, Japan
  • Murakami, Taichi, Tokushima University Hospital, Tokushima, Japan
  • Abe, Hideharu, Tokushima University Hospital, Tokushima, Japan
  • Aihara, Ken-ichi, Tokushima University, Tokushima, Japan
  • Nagai, Kojiro, Tokushima University Hospital, Tokushima, Japan
Background

Medical advances have made it possible to control diseases such as cancer, autoimmune diseases and infectious diseases, extending life for affected patients worldwide. On the other hand, CKD has become a lifestyle-related disease and lifestyle management is necessary to extend healthy life span. In this study, we clarify the effect of interaction between hypertension and atherosclerosis on renal fibrosis and aging.

Methods

Wild type (WT) mouse, apolipoprotein E- / - (ApoE KO) mouse, and endothelial nitric oxide synthase (eNOS) - / - ; ApoE - / - (WKO) mouse were obtained by crossing eNOS +/- mouse and ApoE +/- mouse. Unilateral ureteral obstruction (UUO) was performed on 8-10 weeks old male mice after blood pressure and lipid profile were measured. Mice were sacrificed 10 days after UUO. The degree of renal tubular injury, fibrosis and kidney aging were evaluated among the three groups.

Results

ApoE KO mice had higher total cholesterol and lower HDL cholesterol than WT mice. WKO mice manifested elevated blood pressure, higher total cholesterol and lower HDL cholesterol than WT mice. Compared with WT mice, ApoE KO and WKO mice showed sustained kideny injury molecule-1 expression and increased α-smooth muscle actin protein expression was found in WKO mice after UUO. mRNA expression of transforming growth factor-β, connective tissue growth factor and type 1 collagen was increased both in ApoE KO and WKO mice and the highest in WKO mice with statistical significance. The picro-sirius red positive stained kidney area was significantly higher in ApoE KO mice and WKO mice. The antioxidant, heme oxygenase-1 was significantly decreased in WKO mice. Furthermore, mRNA expression of p53, p21 and p16 were increased both in ApoE KO and WKO mice and the highest in WKO mice among three groups with significance. A significant increase in senescence associated β-gal positive tubule area was observed in WKO mice.

Conclusion

Mice at high risk for cardiovascular disease developed kidney fibrosis and aging even in the young mice after injury. Vulnerability to oxidative stress promotes fibrosis and aging. Managing lifestyle-related diseases from a young age is important for CKD prevention. This mouse model could be a good tool for elucidating the relationship between bad lifestyle and kidney fibrosis and aging.

Funding

  • Government Support - Non-U.S.