Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

Abstract

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/ þ 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.

The cellular origin of laminin determines its role in blood pressure regulation

“…This is consistent with previous studies that SM22α is expressed in aorta [29–31]. In contrast to a previous report that nestin-cre mediated recombination did not occur in heart and aorta [23,32], we demonstrated region-specific expression of nestin in aorta and loss of laminin in nestin + cells in NKO mice.…”

A Pkd1-Fbn1 Genetic Interaction Implicates TGF-β Signaling in the Pathogenesis of Vascular Complications in Autosomal Dominant Polycystic Kidney Disease

“…38,47 Although these reports document abnormalities in the myogenic tone of mesenteric arteries in Pkd1 VSMC2 mice, these groups did not focus on the proximal ascending aorta, which is where we observed reproducible morphologic changes. The predominance of degenerative changes in this area can be explained by the embryonic origin of VSMCs in this part of the aorta.…”

“…This is similar to what has been reported by others using the same Cre recombinase to delete Pkd1. 38 Three independent observers who were blinded to genotype graded aortic histopathology in cohorts of mice (n=8) at 2 and 6 months of age (Supplemental Methods). We focused our analysis on the proximal ascending aorta because this is the area that is most susceptible to dilation in Fbn1 mutant mice.…”

Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

“…A different role for PC1 and PC2 has also been suggested in the vasculature, whereby the ratio of the two proteins regulates pressure sensing, acting through stretch-activated ion channels (77). However, conditional mice generated with loss of PC1 in vascular smooth muscle cells and endothelial cells do not have a clear vascular phenotype (78).…”