Osten, Larissa and Kubitza, Marion and Gallagher, Anna Rachel and Kastner, Juergen and Olbrich, Heike and de Vries, Uwe and Kees, Frieder and Lelongt, Brigitte and Somlo, Stefan and Omran, Heymut and Witzgall, Ralph (2009) Doxycycline accelerates renal cyst growth and fibrosis in the pcy/pcy mouse model of type 3 nephronophthisis, a form of recessive polycystic kidney disease. HISTOCHEMISTRY AND CELL BIOLOGY, 132 (2). pp. 199-210. ISSN 0948-6143, 1432-119X
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MATRIX METALLOPROTEINASES; TISSUE INHIBITORS; PRIMARY CILIUM; C-ELEGANS; IN-VIVO; GENE; CELLS; MICE; TETRACYCLINE; EXPRESSION; Doxycycline; Polycystic kidney disease; Nephronophthisis; Intracellular calcium; Primary cilia |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 615 Pharmacy |
| Divisions: | Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Molekulare und zelluläre Anatomie > Prof. Dr. Ralph Witzgall Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Prof. Frieder Kees |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 Sep 2020 12:35 |
| Last Modified: | 10 Sep 2020 12:35 |
| URI: | https://pred.uni-regensburg.de/id/eprint/28634 |
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