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Inhibition of the TGF? signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis.

ABSTRACT: Agents that enhance production of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) ameliorate the progression of renal fibrosis. However, the molecular mechanism of this process is not fully understood. We hypothesize that the antifibrotic effects of cGMP and cGMP-dependent kinase I (cGKI) are mediated via regulation of the TGF? signalling pathway, both via ERK and the Smad-dependent route. Kidney fibrosis was induced by unilateral ureter obstruction (UUO) in wild-type and cGKI-deficient (cGKI-KO) mice. The cGMP/cGKI signalling pathway was activated by application of the soluble guanylate cyclase (sGC) stimulator BAY 41-8543 (BAY), beginning 1 day after UUO. After 7 days, the antifibrotic effects of BAY were analysed by measuring mRNA and protein expression of characteristic fibrotic biomarkers. The effects of cGMP/TGF? on cultured fibroblasts were also analysed in vitro. BAY application influenced the activity of the extracellular matrix (ECM)-degrading matrix metalloproteases (MMP2 and MMP9) and their inhibitor tissue inhibitors of metalloproteinase-1, the secretion of cytokines (e.g. IL-6) and the expression pattern of ECM proteins (e.g. collagen, fibronectin) and profibrotic mediators (e.g. connective tissue growth factors and plasminogen-activator inhibitor-1). Activation of the cGMP/cGKI signalling pathway showed protective effects against fibrosis which were mediated by inhibition of P-Erk1/2 and translocation of P-smad3. The elucidation of these signalling mechanisms might support the development of new therapeutic options regarding cGMP/cGKI-mediated antifibrotic actions.

SUBMITTER: Schinner E

PROVIDER: S-EPMC5377407 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Inhibition of the TGFβ signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis.

Schinner Elisabeth E Wetzl Veronika V Schramm Andrea A Kees Frieder F Sandner Peter P Stasch Johannes-Peter JP Hofmann Franz F Schlossmann Jens J

FEBS open bio 20170301 4

Agents that enhance production of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) ameliorate the progression of renal fibrosis. However, the molecular mechanism of this process is not fully understood. We hypothesize that the antifibrotic effects of cGMP and cGMP-dependent kinase I (cGKI) are mediated via regulation of the TGFβ signalling pathway, both via ERK and the Smad-dependent route. Kidney fibrosis was induced by unilateral ureter obstruction (UUO) in wild-type and cGKI-defici ...[more]

PMID: 28396839

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Project description:Monosodium urate (MSU) crystallisation deposited in local tissues and organs induce inflammatory reactions, resulting in diseases such as gout. MSU has been recognized as a common and prevalent pathology in various clinical conditions. In this study, we investigated the role of MSU in the pathogenesis of diabetic kidney disease (DKD). We induced renal injury in diabetic kidney disease mice using streptozotocin (STZ) and assessed renal histopathological damage using Masson's trichrome staining and Collagen III immunofluorescence staining. We measured the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and uric acid (UA) using ELISA. Protein expression levels of NLRP3, p-NF-κB, SHP2, p-STAT3, and p-ERK1/2 were analyzed by Western blot. To further investigate the role of MSU in diabetic kidney disease, we conducted in vitro experiments. In our in vivo experiments, we found that compared to the Model group, there was a significant increase in interstitial fibrosis in the kidneys of mice after treatment with MSU, accompanied by elevated levels of MDA, SOD, and UA. Furthermore, the protein expression of NLRP3, p-NF-NB, SHP2, p-STAT3, and p-ERK1/2 was upregulated. In our subsequent studies on mouse fibroblasts (L929 cells), we discovered that high glucose, MSU, and TGF-β could promote the expression of P22, GP91, NLRP3, NF-κB, p-NF-κB, p-SHP2, p-EGFR, p-STAT3, and Collagen-III proteins. Additionally, we found that SHP2 could counteract the upregulation trend induced by MSU on the expression of p-SHP2, p-EGFR, p-STAT3, and Collagen-III proteins, and inhibitors YQ128, NAC, and Cetuximab exhibited similar effects. Furthermore, immunofluorescence results indicated that SHP2 could inhibit the expression of the fibrosis marker α-SMA in L929 cells. These findings suggest that MSU can promote renal fibroblast SHP2 expression, induce oxidative stress, activate the NLRP3/NF-κB pathway, and enhance diabetic kidney disease fibroblast proliferation through the TGFβ/STAT3/ERK1/2 signaling pathway, leading to renal fibrosis.

Dataset Information

Inhibition of the TGF? signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis.

Publications

Inhibition of the TGFβ signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis.

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