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Kidney Week

Abstract: SA-PO998

Deficiency of Angiotensin II Type 1 Receptor Prevents Muscle Atrophy due to Denervation

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Takayama, Suguru, Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
  • Sugaya, Takeshi, Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
  • Shibagaki, Yugo, Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
  • Ikemori, Atsuko, Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
Background

Because chronic kidney disease (CKD) is a high risk of muscle wasting, managing CKD is clinically important for promoting the health and well-being of patients with CKD in aging society. Although angiotensin II (Ang II) type 1 receptor blocker was reported to attenuate muscle atrophy after muscle injury model, its model does not reflect human pathophysiological conditions. The aim of this study is to reveal whether suppressed activation of angiotensin II type 1 receptor (AT1) prevents severe muscle atrophy after denervation which mimics disuse atrophy.

Methods

To induce severe muscle atrophy, the sciatic nerves in right and left inferior limbs were cut in AT1a knockout homo (AT1a-/-) male mice and wild type (AT1a+/+) male mice. Both leg muscle tissues were removed and were categorized as gastrocnemius muscle at 3-, 7- and 21-day post-denervation.

Results

Muscle weight and cross-sectional areas of type IIb muscle fibers in gastrocnemius muscle decreased at 7- and 21-day post-denervation in both AT1a-/- mice and AT1a+/+ mice, and the degree was significantly milder in the denervated muscle of AT1a-/- mice than in the denervated muscle of AT1a+/+ mice. Regarding activation of muscle protein degradation system, upregulated expressions of phosphorylated nuclear factor-kB at 3-day and two E3 ubiquitin ligases (muscle RING-finger protein-1 and atrogin-1) at 7- and 21-day were significantly downregulated in the denervated muscle of AT1a-/- mice compared to the AT1a+/+ mice. In addition, while muscle apoptosis evaluated by gene expressions of Bcl-2-associated X protein and Tunel staining was induced in both AT1a-/- mice and AT1a+/+ mice, the degree was significantly suppressed in the AT1a-/- mice. On the other hand, there were not significantly differences in activations of protein synthesis and autophagy which were evaluated by protein expressions of phosphorylated ribosomal protein S6 kinase b-1 and LC3B-II/I, between the AT1a-/- mice and AT1a+/+ mice.

Conclusion

Inactivation of the AT1 receptor prevented muscle atrophy due to denervation via suppressions of protein degradation system and apoptosis. Ang II type 1 receptor blocker may be useful for prevention of muscle atrophy in elder patients with CKD.