Program

OR30-3

Aquaporin-3 deficiency slows renal cyst growth by impairment of glucose metabolism via AMPK/ERK/mTOR signaling

[Speaker] Baoxue Yang:1
1:Peking University, China

Background: Human autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral renal cysts that lead to a decline in kidney function over time. Previous studies reported aquaporin-3 (AQP3) expression in cysts derived from collecting ducts in ADPKD.
Methods: Two PKD mouse models, kidney-specific Pkd1 knockout mice and inducible Pkd1 knockout mice, were generated with or without AQP3 deletion. MDCK cell line was used to study the mechanism in which AQP3 affected cyst development.
Results: Kidney size and cyst index were significantly smaller in AQP3-null PKD mice than those in AQP3-expressing PKD mice. AQP3 deficiency reduced the number of cysts from collecting duct and their diameter. The diameter of AQP3-MDCK cysts was significantly ~38% larger than in control MDCK cells. The percentage of AQP3-MDCK cells that formed cysts was significantly lower than in control MDCK cells. Western-blot analyses revealed that the expression levels of proliferating cell nuclear antigen in AQP3-null PKD were reduced as compared with the PKD mice. Consistent with the results in vivo, intracellular ATP in AQP3 null kidney was 75% of that in AQP3-expressing kidney. We found lower level of AMPK phosphorylation in AQP3-MDCK cells as compared to MDCK cells. In vivo, the p-AMPK in AQP3 null kidney was 2.4-fold more than that in wild-type kidney. The level of p-AMPK in PKD mouse kidney was half of which in wild-type control kidney. AQP3 gene deletion in PKD mice reversed the p-AMPK level. AQP3 null kidney produced a significant increase in phosphorylated ACC (p-ACC) levels. Western blot revealed that p-S6 in AQP3 null kidney was 17.7% of that in wild-type kidney. The level of p-S6 in PKD mouse kidney was 1.8 fold greater than that in wild-type mouse kidney. AQP3 gene deletion in PKD mice reversed the p-S6 to a normal level.
Conclusion: The experimental results indicate that AQP3 depletion retards cyst growth in part as a consequence of impaired AQP3-dependent energy metabolism. These findings identify AQP3 as a potential target to reduce cyst development in ADPKD.

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