Abstract: PUB107
Mitochondrial AKT1 Signaling and Kidney Injury: Unraveling Mechanistic Insights into Metabolic Syndrome-Induced Kidney Dysfunction
Session Information
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Lin, Hugo Y.-H., Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung, Taiwan
- Ko, Yu-Min, Kaohsiung Medical University, Kaohsiung, Taiwan
- Yang, Ming-Yu, Chang Gung University, Taoyuan, Taiwan
Background
Metabolic syndrome (MetS) is associated with kidney diseases, but the etiology is inconclusive. We hypothesized that renal tubular mitochondrial AKT1 (mito-AKT1) signaling plays a mechanistic role in the pathogenesis of kidney injuries in MetS.
Methods
We executed the study with 8-week C57BL/6 male mice fed a high-fat diet for four months, compared with mice fed a standard chow diet. To examine the role of mito-AKT1 translocation, the cell viability of HK-2 cells treated with heat shock protein 90 (Hsp90) was examined.
Results
In our murine MetS model, body weight significantly increased. The kidney size as a percentage of body weight remained similar between the groups. For the glucose tolerance test, fasting glucose levels were significantly higher in MetS mice than those on a regular diet (p<0.05). From 15 to 120 minutes, glucose levels were consistently elevated. The intraperitoneal glucose tolerance test curve differed between three and six months, with the area under the curve (AUC) value being higher at six months (p=0.013). Fasting hyperinsulinemia and insulin resistance, as measured by the Homeostatic Model Assessment for Insulin Resistance, were also elevated.
Regarding renal function, serum BUN and creatinine levels in MetS mice did not change significantly. However, proteinuria and urine KIM-1 levels were elevated, which indicated renal tubular injuries. Histological examination revealed significant increases in glomerulosclerosis index, tubulointerstitial fibrosis, tubular dilatation, and tubular vacuolation score.
To further investigate the role of mito-AKT1 signaling during MetS in renal tubules, we examined the mito-AKT1 protein. We observed an increased accumulation of phosphorylated AKT1 (p=0.030) in the mitochondria of proximal tubules after MetS. This AKT1 translocation was confirmed using immunohistochemistry staining and western blot analysis of mitochondrial proteins. Cell viability significantly decreased in the group treated with palmitic acid and the Hsp90 inhibitor, compared to the vehicle-treated group (p<0.01).
Conclusion
These findings shed new light on the mechanistic role of renal tubular mito-AKT1 in MetS-induced kidney injuries and may be used to develop new strategies for preventing and treating kidney diseases.
Funding
- Government Support – Non-U.S.