Elevated TGFβ–Smad signalling in experimental Pkd1 models and human patients with polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited renal disease characterized by many fluid-filled cysts and interstitial fibrosis in the kidneys, leading to chronic renal failure. During cystogenesis the renal tubules undergo extensive structural alterations that are accompanied by altered cellular signalling, directly and/or indirectly regulated by the PKD1 and PKD2 proteins. Since transforming growth factor (TGF)-beta signalling modulates cell proliferation, differentiation, apoptosis, adhesion and migration of various cell types, we studied the activation of this signalling pathway in Pkd1-mutant mouse models at different stages of the disease. Therefore, we analysed expression of the TGFbeta-Smad signalling pathway and its target genes in different Pkd1 mutant mouse models in various stages of polycystic disease. Nuclear accumulation of P-Smad2 in cyst lining epithelial cells was not observed in the initiation phase but was observed at mild and more advanced stages of PKD. This coincides with mild fibrosis and increased mRNA levels of TGFbeta target genes, such as fibronectin, collagen type I, plasminogen activator inhibitor 1 and matrix metalloproteinase-2. At this stage many interstitial fibroblasts were found around cysts, which also showed nuclear localization for P-Smad2. However, bone morphogenetic protein (BMP) signalling, which can antagonize TGFbeta signalling, is not affected, since nuclear expression of P-Smad1/5/8 and expression of the BMP target gene, inhibitor of DNA binding/differential-1 (ID-1) is not altered compared to wild-type controls. Also, human kidneys with progressive ADPKD showed increased nuclear localization of P-Smad2, while in general expression of P-Smad1/5/8 was weak. These results exclude TGFbeta signalling at the initiation of cystogenesis, but indicate an important role during cyst progression and in fibrogenesis of progressive ADPKD.

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

“…44 In mouse models in which Pkd1 can be conditionally inactivated, TGF-b signaling was not different from baseline in the early stages of cystogenesis; however, in later phases, cysts lining epithelial cells exhibited increased nuclear staining for pSmad2 along with increased expression of TGF-b target genes such as PAI-1. 45 Our cell culture data suggest that increased TGF-b ligands in the setting of ADPKD might result in an amplified response that could contribute to fibrosis and disease progression. Interestingly, a retrospective study of patients with MFS demonstrated an increased incidence of renal and hepatic cysts compared with an age/sex-matched control population.…”

The Effect of cAMP-PKA Activation on TGF-β1-Induced Profibrotic Signaling

“…Pkd1 mutations lead to an earlier age of onset for ESRD than do Pkd2 mutations [18]. Cyst-lining epithelial cells exhibit increased nuclear staining for phosphorylated Smad2 and increased expression of TGF-β target genes such as collagen type I [19]. Microarray [20] studies of human ADPKD kidneys revealed that TGF-β and its downstream effectors are highly expressed in cystic epithelium.…”

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

“…[1][2][3][4][5] A plethora of cellular changes have been observed in cystic epithelium-like cells or tissues, including aberrant Ras/Raf/ERK activation, cAMP accumulation, as well as altered activation of Gproteins, mammalian target of rapamycin (mTOR), PI3-kinase, Jak2-STAT1/3, NFAT, TGFb, and NF-kb signaling. [6][7][8][9][10][11][12] Although there are currently no reliable therapies available and clinical management of ADPKD is mainly focused on managing complications, it is anticipated that new therapeutic interventions targeting these key molecular changes in PKD might prove effective. Clinical trials testing the efficacy of mTOR inhibitors were recently evaluated.…”

“…11,25,26 These Pkd1 models were used to investigate the effects of low and high doses of sirolimus at different stages of the disease to determine whether a conventional low dose is as effective at reducing cyst formation and fibrosis as a higher dose, whether conventional low-dose sirolimus inhibits mTOR activity in cystic kidneys, and whether sirolimus is equally effective when initiated later in the disease course compared with early administration.…”