4.7 Article

Expression of active B-Raf proto-oncogene in kidney collecting ducts induces cyst formation in normal mice and accelerates cyst growth in mice with polycystic kidney disease

期刊

KIDNEY INTERNATIONAL
卷 102, 期 5, 页码 1103-1114

出版社

ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2022.05.028

关键词

-

资金

  1. National Institute of Diabetes and Digestive and Kidney Diseases [R01DK081579]
  2. PKD Foundation
  3. KU Cancer Center
  4. National Institutes of Health(NIH) Center of Biomedical Research Excellence (COBRE): MolecularRegulation of Cell Development and Differentiation
  5. KansasIDeA Network of Biomedical Research Excellence [P30 CA168524, P30 GM122731, P20 GM103418]
  6. NIH [P30DK079328]

向作者/读者索取更多资源

This study demonstrates that active BRAF is sufficient to induce kidney cyst formation in normal mice and accelerate cystic disease in PKD mice.
Polycystic kidney disease (PKD) is characterized by the formation and progressive enlargement of fluid -filled cysts due to abnormal cell proliferation. Cyclic AMP agonists, including arginine vasopressin, stimulate ERK-dependent proliferation of cystic cells, but not normal kidney cells. Previously, B-Raf proto-oncogene (BRAF), a MAPK kinase kinase that activates MEK-ERK signaling, was shown to be a central intermediate in the cAMP mitogenic response. However, the role of BRAF on cyst formation and enlargement in vivo had not been demonstrated. To determine if active BRAF induces kidney cyst formation, we generated transgenic mice that conditionally express BRAFV600E , a common activating mutation, and bred them with Pkhd1-Cre mice to express active BRAF in the collecting ducts, a predominant site for cyst formation. Collecting duct expression of BRAFV600E (BRafCD) caused kidney cyst formation as early as three weeks of age. There were increased levels of phosphorylated ERK (p-ERK) and proliferating cell nuclear antigen, a marker for cell proliferation. BRafCD mice developed extensive kidney fibrosis and elevated blood urea nitrogen, indicating a decline in kidney function, by ten weeks of age. BRAFV600E transgenic mice were also bred to Pkd1RC/RC and pcy/pcy mice, well-characterized slowly progressive PKD models. Collecting duct expression of active BRAF markedly increased kidney weight/body weight, cyst number and size, and total cystic area. There were increased p-ERK levels and proliferating cells, immune cell infiltration, interstitial fibrosis, and a decline in kidney function in both these models. Thus, our findings demonstrate that active BRAF is sufficient to induce kidney cyst formation in normal mice and accelerate cystic disease in PKD mice.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据