Dataset Information

Blocking TGF-? and ?-Catenin Epithelial Crosstalk Exacerbates CKD.

ABSTRACT: The TGF-? and Wnt/?-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF-? has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF-? signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF-? type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF-? receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF-? receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/?-catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF-? receptor impaired ?-catenin activity in vitro and in vivo Genetically restoring ?-catenin activity in proximal tubules lacking the TGF-? receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF-? receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of ?-catenin activity or an indirect effect of ?-catenin interacting with other growth factors. In conclusion, blocking TGF-? and ?-catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD.

SUBMITTER: Nlandu-Khodo S

PROVIDER: S-EPMC5698068 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Publications

Blocking TGF-β and β-Catenin Epithelial Crosstalk Exacerbates CKD.

Nlandu-Khodo Stellor S Neelisetty Surekha S Phillips Melanie M Manolopoulou Marika M Bhave Gautam G May Lauren L Clark Peter E PE Yang Haichun H Fogo Agnes B AB Harris Raymond C RC Taketo M Mark MM Lee Ethan E Gewin Leslie S LS

Journal of the American Society of Nephrology : JASN 20170712 12

The TGF-β and Wnt/β-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF-β has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF-β signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF-β type 2 r ...[more]

PMID: 28701516

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Project description:Nrf2 and TGF-β1 both affect tumorigenesis in a dual fashion, either by preventing carcinogen induced carcinogenesis and suppressing tumor growth, respectively, or by conferring cytoprotection and invasiveness to tumor cells during malignant transformation. Given the involvement of Nrf2 and TGF-β1 in the adaptation of epithelial cells to persistent inflammatory stress, e.g. of the pancreatic duct epithelium during chronic pancreatitis, a crosstalk between Nrf2 and TGF-β1 can be envisaged. By using premalignant human pancreatic duct cells (HPDE) and the pancreatic ductal adenocarcinoma cell line Colo357, we could show that Nrf2 and TGF-β1 independently but additively conferred an invasive phenotype to HPDE cells, whereas acting synergistically in Colo357 cells. This was accompanied by differential regulation of EMT markers like vimentin, Slug, L1CAM and E-cadherin. Nrf2 activation suppressed E-cadherin expression through an as yet unidentified ARE related site in the E-cadherin promoter, attenuated TGF-β1 induced Smad2/3-activity and enhanced JNK-signaling. In Colo357 cells, TGF-β1 itself was capable of inducing Nrf2 whereas in HPDE cells TGF-β1 per-se did not affect Nrf2 activity, but enhanced Nrf2 induction by tBHQ. In Colo357, but not in HPDE cells, the effects of TGF-β1 on invasion were sensitive to Nrf2 knock-down. In both cell lines, E-cadherin re-expression inhibited the proinvasive effect of Nrf2. Thus, the increased invasion of both cell lines relates to the Nrf2-dependent downregulation of E-cadherin expression. In line, immunohistochemistry analysis of human pancreatic intraepithelial neoplasias in pancreatic tissues from chronic pancreatitis patients revealed strong Nrf2 activity already in premalignant epithelial duct cells, accompanied by partial loss of E-cadherin expression. Our findings indicate that Nrf2 and TGF-β1 both contribute to malignant transformation through distinct EMT related mechanisms accounting for an invasive phenotype. Provided a crosstalk between both pathways, Nrf2 and TGF-β1 mutually promote their tumorigenic potential, a condition manifesting already at an early stage during inflammation induced carcinogenesis of the pancreas.

Dataset Information

Blocking TGF-? and ?-Catenin Epithelial Crosstalk Exacerbates CKD.

Publications

Blocking TGF-<i>β</i> and <i>β</i>-Catenin Epithelial Crosstalk Exacerbates CKD.

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