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Cystic epithelia acquire mesenchymal-like features in polycystic kidney disease (PKD). In this phenotypic alteration, it is well known that transforming growth factor (TGF)-β/Smad3 signaling is involved; however, there is emerging new data on Smad3 phosphoisoforms: Smad3 phosphorylated at linker regions (pSmad3L), COOH-terminal regions (pSmad3C), and both (pSmad3L/C). pSmad3L/C has a pathological role in colorectal cancer. Mesenchymal phenotype-specific cell responses in the TGF-β/Smad3 pathway are implicated in carcinomas. In this study, we confirmed mesenchymal features and examined Smad3 phosphoisoforms in the cpk mouse, a model of autosomal recessive PKD. Kidney sections were stained with antibodies against mesenchymal markers and domain-specific phospho-Smad3. TGF-β, pSmad3L, pSmad3C, JNK, cyclin-dependent kinase (CDK) 4, and c-Myc were evaluated by Western blotting. Cophosphorylation of pSmad3L/C was assessed by immunoprecipitation. α-Smooth muscle actin, which indicates mesenchymal features, was expressed higher in cpk mice. pSmad3L expression was increased in cpk mice and was predominantly localized in the nuclei of tubular epithelial cells in cysts; however, pSmad3C was equally expressed in both cpk and control mice. Levels of pSmad3L, JNK, CDK4, and c-Myc protein in nuclei were significantly higher in cpk mice than in controls. Immunoprecipitation showed that Smad3 was cophosphorylated (pSmad3L/C) in cpk mice. Smad3 knockout/ cpk double-mutant mice revealed amelioration of cpk abnormalities. These findings suggest that upregulating c-Myc through the JNK/CDK4-dependent pSmad3L pathway may be key to the pathophysiology in cpk mice. In conclusion, a qualitative rather than a quantitative abnormality of the TGF-β/Smad3 pathway is involved in PKD and may be a target for disease-specific intervention.

Beppu H, Takayanagi N, Tomita Y, Mizutani K, Orand A, Tamai I, Takahashi H, Sonoda S. Improvement of gait and coordinated movement by forced gait training in cerebellar ataxic B6-wob/t mice. Jpn J Compr Rehabil Sci 2015; 6: 64-70. Objective: The effect of forced gait training was investigated in cerebellar ataxic mice (B6-wob/t) using gait analysis and a rota-rod test. Methods: B6 and B6-wob/t mice were divided into non-exercise (NEx) and exercise (Ex) groups. The Ex group received forced gait training with a running wheel at 2 m/min for 50 minutes, three times a day, six days a week, for 12 weeks. The rota-rod test was performed every 4 weeks during this period, and gait was evaluated using our pelvic axis-based gait analysis method (pelvic axis method) when a significant difference was noted between the NEx and Ex groups. The multiple comparison test was used for statistical analysis. Results: After gait training for 12 weeks, the time until falling in the rota-rod test was significantly extended to 115 seconds in the Ex group compared to that (90 seconds) in the NEx group, and the hindlimb step width measured using the pelvic axis method was significantly narrower in the EX than NEx group. Conclusion: Forced gait training may be effective for ataxic symptoms of B6-wob/t. The combination of the pelvic axis-based gait analysis and rota-rod test was useful to evaluate the improvement of ataxia.

Cystic epithelia acquire mesenchymal-like features in polycystic kidney disease (PKD). In this phenotypic alteration, it is well known that transforming growth factor (TGF)-β/Smad3 signaling is involved; however, there is emerging new data on Smad3 phosphoisoforms: Smad3 phosphorylated at linker regions (pSmad3L), COOH-terminal regions (pSmad3C), and both (pSmad3L/C). pSmad3L/C has a pathological role in colorectal cancer. Mesenchymal phenotype-specific cell responses in the TGF-β/Smad3 pathway are implicated in carcinomas. In this study, we confirmed mesenchymal features and examined Smad3 phosphoisoforms in the