Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant

Abstract

Mutations of either PKD1 or PKD2 are associated with autosomal dominant polycystic kidney disease (ADPKD). The molecular function of the gene product of PKD1, polycystin-1, in vitro has been elucidated recently, but the molecular pathological consequences of the loss of polycystin-1 in vivo have remained unclear. We have generated a mouse with a targeted deletion of exons 2-6 of Pkd1 to study the molecular defects in Pkd1 mutants. Homozygote embryos (Pkd1(-/-)) developed hydrops, cardiac conotruncal defects and renal cystogenesis. Total protein levels of beta-catenin in heart and kidney and c-MYC in heart were decreased in Pkd1(-/-) embryos. In the kidneys of Pkd1(-/-), the expression of E-cadherin and PECAM in basolateral membranes of renal tubules was attenuated, and tyrosine phosphorylation of epidermal growth factor receptor and Gab1 were constitutively enhanced when cystogenesis started on embryonic day (E) 15.5-16.5. Maternally administered pioglitazone, a thiazolidinedione compound, resolved these molecular defects of Pkd1(-/-). Treatment with pioglitazone improved survival of Pkd1(-/-) embryos and ameliorated the cardiac defects and the degree of renal cystogenesis. Long-term treatment with pioglitazone improved the endothelial function of adult Pkd1(+/-). These data indicated that molecular defects observed in Pkd1(-/-) embryos contributed to the pathogenesis of ADPKD and that thiazolidinediones had a compensatory effect on the pathway affected by the loss of polycystin-1. Pathways activated by thiazolidinediones may provide new therapeutic targets in ADPKD.

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

“…33 Several other explanations could be given why without additional triggers the hypomorphic Pkd1 nl/nl mice, and also Pkd1 knock-out mice, show structural abnormalities of the blood vessels at neonatal or embryonic stages, respectively, while the SM22;Tie2-Pkd1 del/del mice do not. 4,10,11,16 The genetic background may affect the process of blood vessel remodeling, as the complex mouse models used in this study consisted of a mixture of different genetic backgrounds. Furthermore, low Pkd1 expression in other cell types than SMCs and Ecs, in which Pkd1 is not disrupted in the SM22;Tie2-Pkd1 del/del mice (for instance immune cells), may contribute to the process of aneurysm formation in Pkd1 nl/nl mice, thereby accelerating the process.…”

“…These cysts were only observed in Pkd1 knock-out mice but not in hypomorphic mice that have low levels of Pkd1 gene expression, suggesting that total absence of Pkd1 is necessary to induce the formation of glomerular cysts. 10,11,15,17,43,44 How these cysts arise is not entirely clear. As Pkd1 is deleted in Bowman's capsule, the suggested mechanism that urinary tract infections lead to increased pressure in Bowman's space seems not very likely in SM22-Pkd1 del/del mice.…”

“…Homozygous Pkd1 and Pkd2 knock-out mice die in utero, around embryonic day 15, because of severe cystic disease, vascular defects and/or abnormalities of the placental labyrinth, whereas heterozygous Pkd1 knock-out mice showed minimal renal cyst formation in adulthood. 4,[10][11][12][13][14][15] Furthermore, we described a Pkd1 mouse (hypomorphic) model, with low expression of Pkd1 showing progressive polycystic kidney disease and aortic dissecting aneurysms, indicating that Pkd1 is implicated in the structural integrity and function of the vasculature. 16,17 In the hypomorphic Pkd1 nl,nl mice a very prominent media thickening was seen in most of the animals analyzed.…”

PKD1 Haploinsufficiency Causes a Syndrome of Inappropriate Antidiuresis in Mice

“…Like other Pkd1-null mutants, the homozygous Pkd1 Ϫ/Ϫ mice die in utero with massive cystic kidneys, hydrops fetalis, and cardiovascular defects (17)(18)(19)(20). By contrast, there is no consistent phenotype in heterozygous Pkd1 ϩ/Ϫ mice that do not develop renal cysts until (in a few individuals) a very old age (21,22).…”

“…In this study, we used a well-established mouse model with a targeted deletion of Pkd1 (Pkd1 ϩ/Ϫ ) (17) to test whether Pkd1 haploinsufficiency causes abnormal water handling and AVP signaling in the CD before cystogenesis and renal failure. Like other Pkd1-null mutants, the homozygous Pkd1 Ϫ/Ϫ mice die in utero with massive cystic kidneys, hydrops fetalis, and cardiovascular defects (17)(18)(19)(20).…”