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Abstract: TH-PO903

Proximal Tubule Angiotensin II Type 1 Receptor-Associated Protein Regulates Kidney Aging and Lifespan Through Sirtuin1-Mediated Pathway

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Yamaji, Takahiro, Yokohama City University, Yokohama, Kanagawa, Japan
  • Uneda, Kazushi, Yokohama City University, Yokohama, Kanagawa, Japan
  • Kinguchi, Sho, Yokohama City University, Yokohama, Kanagawa, Japan
  • Ohki, Kohji, Yokohama City University, Yokohama, Kanagawa, Japan
  • Kobayashi, Ryu, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, Kanagawa, Japan
  • Azushima, Kengo, Yokohama City University, Yokohama, Kanagawa, Japan
  • Wakui, Hiromichi, Yokohama City University, Yokohama, Kanagawa, Japan
  • Toya, Yoshiyuki, Yokohama City University, Yokohama, Kanagawa, Japan
  • Tamura, Kouichi, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, Kanagawa, Japan
Background

The kidney is easily affected by aging-associated changes including tubulointerstitial fibrosis and tubular atrophy. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP), which was originally identified as a molecule that binds to AT1R, is highly expressed in the kidney. Previously, we have shown that ATRAP suppresses hyper-activation of AT1R signaling, but does not affect the physiological AT1R signaling pathway. This time, we hypothesized that proximal tubule ATRAP suppresses aging-related kidney fibrosis through Sirtuin1-mediated pathway independent of angiotensin signaling.

Methods


ATRAP-knockout mice (KO mice) and their wild-type control mice (WT mice) were fed the standard diet and maintained until death to estimate their life spans. Their growth, physiological parameters and aging-related organ damages in the hearts, aortas and kidneys were analyzed in both groups. To further investigate the mechanism exacerbating aging-related kidney fibrosis in KO mice, the expression of the pro-survival genes was examined using human tubular epithelial cells.

Results

KO mice exhibit a normal age-associated appearance without any evident alterations in physiological parameters, including blood pressure and cardiovascular and metabolic phenotypes. However, in KO mice compared with wild-type mice, the following takes place: (1) age-associated renal function decline and tubulointerstitial fibrosis are more enhanced; (2) renal tubular mitochondrial abnormalities and subsequent increases in the production of reactive oxygen species are more advanced; and (3) lifespan is 18.4% shorter (median lifespan: 100.4 vs. 123.1 week). As a key mechanism, age-related pathological changes in the kidney of KO mice correlated with decreased expression of the pro-survival gene Sirtuin1. Furthermore, in cultured human proximal tubular epithelial cells, deletion of ATRAP also downregulated mRNA expression levels of Sirtuin1 under serum starvation condition.

Conclusion


These results indicate that proximal tubule ATRAP regulates renal Sirtuin1 expression and plays an important role in inhibiting aging-related kidney changes and protecting the normal lifespan.