Abstract: FR-PO291
Associations between Renin-Angiotensin System and Abnormal Renal Energy Metabolism in a Mouse Model of Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic - 1
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Azushima, Kengo, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
- Taguchi, Shinya, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
- Morita, Ryutaro, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
- Nomura, Kenta, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
- Kawasoe, Kentaro, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
- Wakui, Hiromichi, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
- Tamura, Kouichi, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Background
Renin-angiotensin system (RAS) has been a hallmark of the pathogenesis of diabetic kidney disease (DKD), but its underlying mechanisms remain unclear. Recently, abnormal renal energy metabolism has been reported as a novel pathogenesis of DKD. To investigate the association between the RAS and renal energy metabolism, we generated a mouse model of DKD characterized by systemic RAS activation.
Methods
We generated a mouse model of DKD with underlying activation of the RAS by systemic deficiency of angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP), an endogenous suppressor of AT1R signaling, in combination with Ang II stimulation on streptozotocin (STZ)-induced type I diabetes. DKD and non-diabetic control (Ctrl) mice were euthanized to evaluate renal injuries after measurements of urinary albumin excretion (UAE). Renal energy metabolism was estimated by real-time quantitative PCR and western blotting analyses.
Results
A combination of ATRAP deletion with Ang II stimulation in STZ-infused C57BL/6 mice resulted in advanced DKD which had features of human DKD, including overt albuminuria (UAE, Ctrl vs DKD: 10.6±2.0 vs 852.0±195.6 μg/day, p<0.001), glomerular hypertrophy, podocyte loss, mesangial expansion, renal interstitial fibrosis, and functional insufficiency, concomitant with increased angiotensinogen and AT1R expression in the kidneys. Compared to the Ctrl mice, mRNA expression of PGC-1α, a key regulator of mitochondrial metabolism, was significantly increased in DKD mice. In addition, western blotting analysis showed that protein levels of phosphorylated AMPK in DKD mice were significantly decreased, indicating a substantial abnormality of renal energy metabolism in the mouse model of DKD.
Conclusion
Systemic RAS activation induced by the combination of ATRAP deletion with Ang II stimulation accelerated the development of DKD in STZ-induced type I diabetes. In their kidneys, local RAS activity was upregulated along with a perturbation of mitochondrial energy metabolism. Taken together, our findings suggest substantial associations between the RAS and abnormal renal energy metabolism, which might be involved in the underlying mechanisms contributing to the development of DKD.
Funding
- Government Support – Non-U.S.