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Abstract: TH-PO199

Combination of Systemic ATRAP Deletion With Angiotensin II Stimulation Exacerbates Diabetic Nephropathy in Streptozotocin-Induced Diabetic Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Taguchi, Shinya, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  • Azushima, Kengo, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  • Wakui, Hiromichi, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  • Suzuki, Toru, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  • Urate, Shingo, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  • Abe, Eriko, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  • Tanaka, Shohei, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  • Tsukamoto, Shunichiro, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  • Tamura, Kouichi, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Background

One of the obstacles to understanding the pathophysiology of diabetic nephropathy (DN) has been the lack of reliable animal models that replicate features of human DN. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R from the cell surface into the cytoplasm, resulting in the suppression of the AT1R signaling pathway. We have recently reported that systemic ATRAP deletion exaggerates streptozotocin (STZ)-induced DN via activation of the renal renin-angiotensin system (Haruhara K, et al. Kidney Int 2022). However, the increase in albuminuria in STZ-induced diabetic ATRAP knockout mice is still modest with limited pathological changes in glomerulus. To establish more robust DN models, we examined the effect of Ang II stimulation on the development of DN in STZ-treated ATRAP knockout mice.

Methods

Eight-week-old male C57BL/6 mice (Ctrl) and systemic ATRAP-knockout mice (KO) were divided into three groups: 1) Ctrl-STZ, 2) Ctrl-STZ-Ang II, and 3) KO-STZ-Ang II. Hyperglycemia was induced by intraperitoneal injection of 55 mg/kg STZ for consecutive 5 days. From 4 weeks after STZ, Ang II (1000 ng/kg/min) was continuously administered for 6 weeks. During the experimental period, body weight (BW)s and blood glucose (BG) were measured every 2 weeks. At the end of the experimental period, 24-hour urine samples were collected, and mice were euthanized to evaluate renal pathological changes.

Results

During the experimental period, BW gain and BG were not significantly different between the three groups. Nonetheless, the KO-STZ-Ang II group exhibited a remarkable increase in the urinary albumin excretion levels compared to the Ctrl-STZ and Ctrl-STZ-Ang II groups at the end of the experimental period (679.1±583.7 vs 69.9±10.0 vs 61.3±8.2 μg/day, respectively). Furthermore, the histopathological analysis revealed a worsening of DN, an exacerbation of mesangial expansion and interstitial fibrosis, in the KO-STZ-Ang II group.

Conclusion

The results of present study showed that systemic ATRAP deletion in combination with Ang II stimulation accelerated the development of DN in STZ-induced diabetic mice, suggesting a potential to become a promising mouse model replicating key features of human DN.