Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension.
Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder characterized by renal, hepatic and pancreatic cyst formation and cardiovascular complications. The condition is caused by mutations in the PKD1 or PKD2 gene. In mice with reduced expression of Pkd1, dissecting aneurysms with prominent media thickening have been seen. To study the effect of selective disruption of Pkd1 in vascular smooth muscle cells (SMCs), we have generated mice in which a floxed part of the Pkd1 gene was deleted by Cre under the control of the SM22 promotor (SM22-Pkd1(del/del) mice). Cre activity was confirmed by X-gal staining using lacZ expressing Cre reporter mice (R26R), and quantitative PCR indicated that in the aorta Pkd1 gene expression was strongly reduced, whereas Pkd2 levels remained unaltered. Histopathological analysis revealed cyst formation in pancreas, liver and kidneys as the result of extravascular Cre activity in pancreatic ducts, bile ducts and in the glomerular Bowman's capsule. Remarkably, we did not find any spontaneous gross structural blood vessel abnormalities in mice with somatic Pkd1 gene disruption in SMCs or simultaneous disruption of Pkd1 in SMCs and endothelial cells (ECs). Extensive isometric myographic analysis of the aorta did not reveal differences in response to KCl, acetylcholine, phenylephrin or serotonin, except for a significant increase in contractility induced by phenylephrin on arteries from 40 weeks old Pkd1(del/+) germ-line mice. However, SM22-Pkd1(del/del) mice showed significantly reduced decrease in heart rate on angiotensin II-induced hypertension. The present findings further demonstrate in vivo, that adaptation to hypertension is altered in SM22-Pkd1(del/del) mice.
Hassane
Sabrine
S
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Claij
Nanna
N
Jodar
Martine
M
Dedman
Alexandra
A
Lauritzen
Inger
I
Duprat
Fabrice
F
Koenderman
Jorine S
JS
van der Wal
Annemieke
A
Breuning
Martijn H
MH
de Heer
Emile
E
Honore
Eric
E
DeRuiter
Marco C
MC
Peters
Dorien J M
DJ
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006339:Heart Rate; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
D008840:Microfilament Proteins; D009124:Muscle Proteins; D050396:TRPP Cation Channels; C051615:transgelin