Segmental cystogenesis and haploinsufficiency in a Pkd1 mouse model of autosomal dominant polycystic kidney disease

Polycystic kidney disease (PKD) is a life threatening, progressive genetic disorder characterized by the presence and growth of numerous bilateral renal cysts. Autosomal dominant polycystic kidney disease (ADPKD) results from loss-of-function mutations in either two genes: PKD1 (in ~85% of cases) or PKD2 (in ~15% of cases). There is currently no treatment that can interfere with process of cystogenesis. However, significant progresses have been made that have offered hope for slowing or stopping the progression of this disease. In the first part of our studies, we have analysed the effect of Pkd1 deletion on the time-course and pattern of cystogenesis and the manifestations of tubular dysfunction as reflected in amniotic fluid composition. Our data demonstrate that the segmental cystogenesis in our Pkd1-null mouse model (Muto et al, 2002) is consistent with the pattern of Pkd1 expression in wild-type mice during nephrogenesis. The lack of polycystin-1, the protein encoding Pkd1 (PC1), does not prevent nephrogenesis but is reflected by cystogenesis, potentially reflecting the sequential expression of Pkd1 in all segments of mouse nephron. We further show that Pkd1-null embryos are characterized by an early and significant loss of solutes in the amniotic fluid, including markers of proximal tubule function. These functional changes precede the development of renal cysts, first from the glomerulus and the proximal tubule, and later extend to distal nephron segments. These studies provide new insights into the potential roles of PC1 in renal development and the mechanisms of cystogenesis, and the functional alterations encountered in ADPKD. In the second part of this thesis, we assessed the PC1 effect on the V2R and Ca2+ signaling pathway. We used a mouse model to investigate the effect of Pkd1 haploinsufficiency on water handling and AVP signaling in the collecting duct. Our data revealed for the first time that, in absence of cystic changes, reduced Pkd1 gene dosage is associated with a syndrome of inappropriate antidiuresis (positive water balance) reflecting decreased intracellular Ca2+ concentration, decreased activity of RhoA, recruitment of AQP2 in the CD, and inappropriate expression of AVP in the brain. These studies present novel data that give additional insights in the potential roles of PC1 in the AVP and Ca2+ signalling and the trafficking of AQP2 in the renal CD.Thèse de doctorat en sciences biomédicales (physiopathologie, biologie moléculaire) (SBIM 3) -- UCL, 200