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Pharmacological correction of a defect in PPAR-γ signaling ameliorates disease severity in Cftr-deficient mice

Nature Medicine volume 16, pages 313–318 (2010)Cite this article

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Abstract

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport1. Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs2 as well as numerous other abnormalities that include inflammation of affected organs1, alterations in lipid metabolism3 and insulin resistance4. Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator–activated receptor-γ (PPAR-γ, encoded by Pparg) function that contributes to a pathological program of gene expression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-γ ligand 15-keto-prostaglandin E2 (15-keto-PGE2). Treatment of Cftr-deficient mice with the synthetic PPAR-γ ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention. These studies reveal a reversible defect in PPAR-γ signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.

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Figure 1: Effect of PPAR-γ activation on the cystic fibrosis intestinal phenotype in mice.
Figure 2: PPAR-γ function and CFTR intestinal phenotype.
Figure 3: Effect of rosiglitzone on Car4 and Car2 expression and bicarbonate transport.
Figure 4: Molecular analysis of PPAR-γ function in Cftr−/− colonic epithelial cells.

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Acknowledgements

We thank P. Quinton for advice and critical reading of the manuscript. We thank the late J. Isenberg (University of California–San Diego) for providing Cftrtm1Unc mice, R. Sasik for assistance with microarray data analysis and D. McCole for assistance with chloride transport studies. Microarray analysis was performed at the Biogem Core Facility of the University of California–San Diego, and histopathology was performed by the University of California–San Diego Histopathology Core Facility. These studies were supported by US National Institutes of Health grants P01DK074868, GM 069338-03 and DK063491 to C.K.G. and E.A.D.; US National Institutes of Health grant DK007202 and Fellowship to Faculty Transition Award from the Foundation for Digestive Health and Nutrition to G.S.H.

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Authors and Affiliations

  1. Department of Medicine, University of California–San Diego, La Jolla, California, USA

    Gregory S Harmon, Kim E Barrett, Hui Dong & Christopher K Glass

  2. Department of Chemistry and Biochemistry, University of California–San Diego, La Jolla, California, USA

    Darren S Dumlao & Edward A Dennis

  3. Department of Pharmacology, University of California–San Diego, La Jolla, California, USA

    Darren S Dumlao & Edward A Dennis

  4. Department of Cellular and Molecular Medicine, University of California–San Diego, La Jolla, California, USA

    Damian T Ng & Christopher K Glass

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  1. Gregory S Harmon
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Contributions

G.S.H. wrote the manuscript and conducted the breeding, survival, histology, chloride ion transport, gene expression and ChIP experiments. D.S.D. performed the lipidomic analysis by mass spectrometry. D.T.N. performed western blot and luciferase assays. H.D. conducted the bicarbonate ion transport experiments. K.E.B. and E.A.D. contributed to experimental design and data analysis and edited the manuscript. C.K.G. supervised the project, analyzed data and edited the manuscript.

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Correspondence to Gregory S Harmon or Christopher K Glass.

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The authors declare no competing financial interests.

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Harmon, G., Dumlao, D., Ng, D. et al. Pharmacological correction of a defect in PPAR-γ signaling ameliorates disease severity in Cftr-deficient mice. Nat Med 16, 313–318 (2010). https://doi.org/10.1038/nm.2101

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