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Renal fibrosis is not reduced by blocking transforming growth factor-? signaling in matrix-producing interstitial cells.

ABSTRACT: Transforming growth factor-? (TGF-?) strongly promotes renal tubulointerstitial fibrosis, but the cellular target that mediates its profibrotic actions has not been clearly identified. While in vitro data suggest that TGF-?-induced matrix production is mediated by renal fibroblasts, the role of these cells in TGF-?-dependent tubulointerstitial fibrosis following renal injury is not well defined. To address this, we deleted the TGF-? type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre that targets medullary interstitial cells, and either the mouse unilateral ureteral obstruction or the aristolochic acid renal injury model. Renal interstitial cells lacking the TGF-? receptor had significantly impaired collagen I production, but, unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury. Thus, abrogating TGF-? signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury.

SUBMITTER: Neelisetty S

PROVIDER: S-EPMC4556568 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells.

Neelisetty Surekha S Alford Catherine C Reynolds Karen K Woodbury Luke L Nlandu-Khodo Stellor S Yang Haichun H Fogo Agnes B AB Hao Chuan-Ming CM Harris Raymond C RC Zent Roy R Gewin Leslie L

Kidney international 20150311 3

Transforming growth factor-β (TGF-β) strongly promotes renal tubulointerstitial fibrosis, but the cellular target that mediates its profibrotic actions has not been clearly identified. While in vitro data suggest that TGF-β-induced matrix production is mediated by renal fibroblasts, the role of these cells in TGF-β-dependent tubulointerstitial fibrosis following renal injury is not well defined. To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using t ...[more]

PMID: 25760325

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Project description:BackgroundThe role of the IL6 family members in organ fibrosis, including renal interstitial fibrosis (TIF), has been widely explored. However, few studies have ever simultaneously examined them in the same cohort of patients. Besides, the role of leukemia inhibitory factor (LIF) in TIF remains unclear.MethodsRNA-seq data of kidney biopsies from chronic kidney disease (CKD) patients, in both public databases and our assays, were used to analyze transcript levels of IL6 family members. Two TIF mouse models, the unilateral ureteral obstruction (UUO) and the ischemia reperfusion injury (IRI), were employed to validate the finding. To assess the role of LIF in vivo, short hairpin RNA, lenti-GFP-LIF was used to knockdown LIF receptor (LIFR), overexpress LIF, respectively. LIF-neutralizing antibody was used in therapeutic studies. Whether urinary LIF could be used as a promising predictor for CKD progression was investigated in a prospective observation patient cohort.FindingsAmong IL6 family members, LIF is the most upregulated one in both human and mouse renal fibrotic lesions. The mRNA level of LIF negatively correlated with eGFR with the strongest correlation and the smallest P value. Baseline urinary concentrations of LIF in CKD patients predict the risk of CKD progression to end-stage kidney disease by Kaplan-Meier analysis. In mouse TIF models, knockdown of LIFR alleviated TIF; conversely, overexpressing LIF exacerbated TIF. Most encouragingly, visible efficacy against TIF was observed by administering LIF-neutralizing antibodies to mice. Mechanistically, LIF-LIFR-EGR1 axis and Sonic Hedgehog signaling formed a vicious cycle between fibroblasts and proximal tubular cells to augment LIF expression and promote the pro-fibrotic response via ERK and STAT3 activation.InterpretationThis study discovered that LIF is a noninvasive biomarker for the progression of CKD and a potential therapeutic target of TIF.FundingsStated in the Acknowledgements section of the manuscript.

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Renal fibrosis is not reduced by blocking transforming growth factor-? signaling in matrix-producing interstitial cells.

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Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells.

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