Disruption of the caveolin-1 gene impairs renal calcium reabsorption and leads to hypercalciuria and urolithiasis.
Using LoxP/Cre technology, we generated a knockout mouse homozygous for a null mutation in exon 2 of Cav1. In male Cav1-/- animals, we observed a dramatic increase in the incidence of urinary calcium stone formation. In 5-month-old male mice, the incidence of early urinary calculi was 67% in Cav1-/- mice compared to 19% in Cav1+/+ animals. Frank stone formation was observed in 13% of Cav1-/- males but was not seen in Cav1+/+ mice. Urine calcium concentration was significantly higher in Cav1-/- male mice compared to Cav1+/+ mice. In Cav1-/- mice, distal convoluted tubule cells were completely devoid of Cav1 and the localization of plasma membrane calcium ATPase was disrupted. Functional studies confirmed that active calcium absorption was significantly reduced in Cav1-/- compared to Cav1+/+ male mice. These results demonstrate that disruption of the Cav1 gene promotes the progressive steps required for urinary calcium stone formation and establish a new mouse model for urinary stone disease.
Cao
Guangwen
G
Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
Yang
Guang
G
Timme
Terry L
TL
Saika
Takashi
T
Truong
Luan D
LD
Satoh
Takefumi
T
Goltsov
Alexei
A
Park
Sang Hee
SH
Men
Taoyan
T
Kusaka
Nobuyuki
N
Tian
Weihua
W
Ren
Chengzhen
C
Wang
Hongyu
H
Kadmon
Dov
D
Cai
Wei Wen
WW
Chinault
A Craig
AC
Boone
Timothy B
TB
Bradley
Allan
A
Thompson
Timothy C
TC
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000652:urine*; D002128:Calcium Metabolism Disorders / Q000235:genetics / Q000473:pathology*; D051242:Caveolin 1; D022461:Caveolins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D003404:Creatinine / Q000652:urine; D017931:DNA Primers; D004195:Disease Models, Animal; D005091:Exons; D007668:Kidney / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping; D014545:Urinary Calculi / Q000235:genetics / Q000473:pathology*
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D017931:DNA Primers; D003404:Creatinine; D002118:Calcium