Doxycycline accelerates renal cyst growth and fibrosis in the pcy/pcy mouse model of type 3 nephronophthisis, a form of recessive polycystic kidney disease.
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-PK(1) 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-PK(1) 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.
Osten
Larissa
L
Institute for Molecular and Cellular Anatomy, University of Regensburg, Universitätsstrasse 31, 93053, Regensburg, Germany.
Kubitza
Marion
M
Gallagher
Anna Rachel
AR
Kastner
Jürgen
J
Olbrich
Heike
H
de Vries
Uwe
U
Kees
Frieder
F
Lelongt
Brigitte
B
Somlo
Stefan
S
Omran
Heymut
H
Witzgall
Ralph
R
D000818:Animals; D003560:Cysts / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005355:Fibrosis; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D007690:Polycystic Kidney Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis* / Q000235:genetics
D061965:Matrix Metalloproteinase Inhibitors; C484365:Pkhd1 protein, mouse; D011956:Receptors, Cell Surface; D019716:Tissue Inhibitor of Metalloproteinase-2; D004318:Doxycycline