Renal cyst and aneurysm formation in polycystic kidney disease mouse models

Abstract

In this thesis we analyzed the pathogenetic sequence of renal cyst and aneurysm formation in PKD mouse models. Cyst formation in the mouse model, Pkd1nl/nl with reduced Pkd1 transcripts was studied by analyzing tubular cell proliferation, apoptosis, extracellular matrix remodeling, and the expression the Na+K+2Cl- co-transporter. These mice presented with a rapidly progressive phenotype and, in time, cyst formation was nephron segment-dependent. Interestingly, the expression of Na+K+2Cl- co-transporters was also segment-dependent. TGF__ signaling, the most important cytokine involved in fibrosis, is activated at the progressive stages of the disease and coincides with mild fibrosis and increased expression of TGF__ target genes. These results suggest that the TGF__ signaling pathway is probably not implicated in initial steps of cyst formation, but indicate an important role during cyst progression and in fibrogenesis of progressive ADPKD. Aneurysm formation was found in the Pkd1nl/nl, indicating a direct association between Pkd1 and vessel wall integrity. But, selective disruption of Pkd1 in vascular smooth muscle cells (SM22-Pkd1del/de micel) did not induce any gross structural blood vessel abnormalities. However, SM22-Pkd1del/del mice significantly showed reduced decrease in heart rate upon Angiotensin II-induced hypertension. These findings further demonstrate in vivo, that adaptation to hypertension is altered in SM22-Pkd1del/del mice.