title: Epithelial cell TGFβ signaling induces acute tubular injury and interstitial inflammation.
abstract: TGFβ signaling plays a central role in the development of acute and chronic kidney diseases. Previous in vivo studies involved systemic alteration of TGFβ signaling, however, limiting conclusions about the direct role of TGFβ in tubular cell injury. Here, we generated a double transgenic mouse that inducibly expresses a ligand-independent constitutively active TGFβ receptor type 1 (TβR1) kinase specifically in tubular epithelial cells, with expression restricted by the Pax8 promoter. In this model, activation of TGFβ signaling in the tubular epithelium alone was sufficient to cause AKI characterized by marked tubular cell apoptosis and necrosis, oxidative stress, dedifferentiation and regenerative cell proliferation, reduced renal function, and interstitial accumulation of inflammatory cells. This tubular injury was associated with mitochondrial-derived generation of reactive oxygen species (ROS), but cell damage and apoptosis were partially independent of mitochondrial-derived ROS. TβR1 signaling-induced tubular injury also associated with significant leukocyte infiltration consisting of F4/80(+) macrophages, CD11c(+) F4/80(+) dendritic cells, CD11c(+) F4/80(-) Ly6C(high) dendritic cells/monocytes, and T cells. Inhibition of mitochondrial-derived ROS significantly reduced accumulation of CD11c(+) F4/80(+) dendritic cells and T cells, suggesting a role for ROS in the activation and recruitment of the adaptive immune response to tubular injury. Taken together, these results suggest that TGFβ signaling in the tubular epithelium alone is sufficient to cause acute tubular injury and inflammation; therefore, TGFβ may be a mechanistic link between acute injury and chronic progression of kidney disease.
authors.affiliation: Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA.
authors.forename: Madeleine E
authors.initials: ME
authors.lastname: Gentle
authors.forename: Shaolin
authors.initials: S
authors.lastname: Shi
authors.forename: Ilse
authors.initials: I
authors.lastname: Daehn
authors.forename: Taoran
authors.initials: T
authors.lastname: Zhang
authors.forename: Haiying
authors.initials: H
authors.lastname: Qi
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: Detlef O
authors.initials: DO
authors.lastname: Schlondorff
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Bottinger
mesh_terms: D000208:Acute Disease; D056704:Adaptive Immunity; D000818:Animals; D017209:Apoptosis; D039521:CD11c Antigen / Q000032:analysis; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000502:physiology; D003713:Dendritic Cells / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology*; D007962:Leukocytes / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009395:Nephritis, Interstitial / Q000209:etiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D039521:CD11c Antigen; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017382:Reactive Oxygen Species; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
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