Abstract
BackgroundInterstitial fibrosis plays an important role in progressive renal dysfunction in autosomal dominant polycystic kidney disease (ADPKD). In our previous studies, we confirmed that PPAR-γ agonist, rosiglitazone could protect renal function and prolong the survival of a slowly progressive ADPKD animal model by reducing renal fibrosis. However, the mechanism remains unknown.MethodsPrimary culture epithelial cells pretreated with TGF-β1 were incubated with rosiglitazone. Extracellular matrix proteins were detected using real-time PCR and Western blotting. MAPK and Smad2 phosphorylation were measured with western blot. ERK1/2 pathway and P38 pathway were inhibited with the specific inhibitors PD98059 and SB203580. The Smad2 pathway was blocked with the siRNA. To address whether PPAR-γ agonist-mediated inhibition of TGF-β1–induced collagen type I expression was mediated through a PPAR-γ dependent mechanism, genetic and pharmaceutical approaches were used to block the activity of endogenous PPARγ.ResultsTGF-β1-stimulated collagen type I and fibronectin expression of ADPKD cyst-lining epithelia were inhibited by rosiglitazone in a dosage-dependent manner. Smad2, ERK1/2 and P38 pathways were activated in response to TGF-β1; however, TGF-β1 had little effect on JNK pathway. Rosiglitazone suppressed TGF-β1 induced Smad2 activation, while ERK1/2 and P38MAPK signals remained unaffected. Rosiglitazone could also attenuate TGF-β1-stimulated collagen type I and fibronectin expression in primary renal tubular epithelial cells, but had no effect on TGF-β1–induced activation of Smad2, ERK1/2 and P38 pathways. There was no crosstalk between the Smad2 and MAPK pathways in ADPKD cyst-lining epithelial cells. These inhibitory effects of rosiglitazone were reversed by the PPARγ specific antagonist GW9662 and PPARγ siRNA.ConclusionADPKD cyst-lining epithelial cells participate in TGF-β1 mediated fibrogenesis. Rosiglitazone could suppress TGF-β1–induced collagen type I and fibronectin expression in ADPKD cyst-lining epithelia through modulation of the Smad2 pathway. Our study may provide therapeutic basis for clinical applications of rosiglitazone in retarding the progression of ADPKD.
Highlights
The cysts gradually increase in number and size over time which is accompanied by interstitial fibrosis and decline of renal function[2,3] While the cystogenesis itself is thought to be a primary driver of organ injury, several studies have pointed out the correlation between the interstitial fibrosis and the progression of autosomal dominant polycystic kidney disease (ADPKD) [5,6,7]
Since collagen type I and fibronectin were the major extracellular matrix (ECM) components of ADPKD kidney tissues [33], we investigated whether rosiglitazone could prevent TGFb1-induced ECM components in ADPKD cyst-lining epithelial cells
Our current study evaluated whether Transforming growth factor-b1 (TGF-b1) could activate mitogen-activated protein kinase (MAPK) pathways in ADPKD cyst-lining epithelial cells
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threaten hereditary disease, caused by mutations of either PKD1 or PKD2 which respectively encode polycystin-1 (PC1) and polycystin-2 (PC2) [1].It affects 1 : 400 to 1 : 1000 live births and accounts for up to 10% of all patients on renal replacement therapy[2,3]. Transforming growth factor-b1 (TGF-b1) is one of the most important cytokines that participate in tubulointerstitial inflammation and fibrosis [8,9]. It exerts its multiple biologic actions by activating several intracellular signal transduction systems including Smad-dependent [10] and Smad-independent pathways such as the mitogen-activated protein kinase (MAPK) pathways, including extracellular signal–regulated kinase (ERK) [11,12,13], Jun N-terminal kinase (JNK) [14], and p38 mitogen–activated protein kinase (p38 MAPK) [15]. Interstitial fibrosis plays an important role in progressive renal dysfunction in autosomal dominant polycystic kidney disease (ADPKD).
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