Doxycycline accelerates renal cyst growth and fibrosis in the pcy/pcy mouse model of type 3 nephronophthisis, a form of recessive polycystic kidney disease
Doxycycline accelerates renal cyst growth and fibrosis in the pcy/pcy mouse model of type 3 nephronophthisis, a form of recessive polycystic kidney disease
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DOI：
10.1007/s00418-009-0588-y
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发表时间：
2009-08-01
影响因子：
2.3
通讯作者：
Witzgall, Ralph
中科院分区：
文献类型：
--
作者：
Osten, Larissa;Kubitza, Marion;Witzgall, Ralph
肾小球肾炎属于隐性囊性肾病家族，可能由多个基因突变引起。在这份报告中，我们使用了一个自发的3型肾炎小鼠突变体来检测多西环素诱导的TIMP-2的合成是否可以影响转基因小鼠的肾囊肿生长。金属蛋白酶在囊性肾脏疾病的进展中可能起到或负或正的作用，我们推测这可能是通过使用天然抑制剂进行检查的最有效的方法。令人惊讶的是，多西环素的应用已经加速了肾囊肿的生长，并导致了肾脏纤维化的增加，TIMP-2的另一种作用没有被检测到。多西环素对肾脏大小的积极作用不是由于非特异性的“合成代谢效应”，而是针对囊性肾，因为它在非囊性肾中没有观察到。在寻找潜在的代谢变化时，我们注意到对照组动物的尿液导致LLC-PK1细胞的钙反应增加，而多西环素处理的小鼠的尿液则表现出相反的作用，甚至拮抗对照组动物的尿液。进一步的实验证明，对照组动物的尿液中含有一种耐热的、抗蛋白酶K的物质，这种物质似乎与诱导LLC-PK1细胞的钙反应有关。我们得出结论，多西环素可能通过诱导一种降低细胞内钙浓度的物质来加速包囊生长。我们的数据在解释基于TET系统的动物模型的表型时也增加了一个注意事项。
Nephronophthisis belongs to a family of recessive cystic kidney diseases and may arise from mutations in multiple genes. In this report we have used a spontaneous mouse mutant of type 3 nephronophthisis to examine whether the doxycycline-inducible synthesis of Timp-2, a natural inhibitor of matrix metalloproteinases, can influence renal cyst growth in transgenic mice. Metalloproteinases may exert either a negative or a positive effect on the progression of cystic kidney disease, and we reasoned that this may be most effectively examined by using a natural inhibitor. Surprisingly, already the application of doxycycline, which also inhibits matrix metalloproteinases, accelerated renal cyst growth and led to increased renal fibrosis, an additional effect of Timp-2 was not detected. The positive effect of doxycycline on kidney size was not due to a non-specific "anabolic effect" but was specific for cystic kidneys because it was not observed in non-cystic kidneys. When looking for potential metabolic changes we noticed that the urine of control animals led to an increase in the calcium response of LLC-PK1 cells, whereas the urine of doxycycline-treated mice showed the opposite effect and even antagonized the urine of control animals. Further experiments demonstrated that the urine of control animals contained a heat-labile, proteinase K-resistant substance which appears to be responsible for the induction of a calcium response in LLC-PK1 cells. We conclude that doxycycline accelerates cyst growth possibly by the induction of a substance which lowers the intracellular calcium concentration. Our data also add a note of caution when interpreting phenotypes of animal models based upon the tet system.