title: Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis.
abstract: Chronic kidney disease (CKD) remains one of the leading causes of death in the developed world, and acute kidney injury (AKI) is now recognized as a major risk factor in its development. Understanding the factors leading to CKD after acute injury are limited by current animal models of AKI, which concurrently target various kidney cell types including epithelial, endothelial, and inflammatory cells. Here, we developed a mouse model of kidney injury using the Six2-Cre-LoxP technology to selectively activate expression of the simian diphtheria toxin (DT) receptor in renal epithelia derived from the metanephric mesenchyme. By adjusting the timing and dose of DT, a highly selective model of tubular injury was created to define the acute and chronic consequences of isolated epithelial injury. The DT-induced sublethal tubular epithelial injury was confined to the S1 and S2 segments of the proximal tubule rather than being widespread in the metanephric mesenchyme-derived epithelial lineage. Acute injury was promptly followed by inflammatory cell infiltration and robust tubular cell proliferation, leading to complete recovery after a single toxin insult. In striking contrast, three insults to renal epithelial cells at 1-week intervals resulted in maladaptive repair with interstitial capillary loss, fibrosis, and glomerulosclerosis, which was highly correlated with the degree of interstitial fibrosis. Thus, selective epithelial injury can drive the formation of interstitial fibrosis, capillary rarefaction, and potentially glomerulosclerosis, substantiating a direct role for damaged tubule epithelium in the pathogenesis of CKD.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. igrgic@rics.bwh.harvard.edu
authors.forename: Ivica
authors.initials: I
authors.lastname: Grgic
authors.forename: Gabriela
authors.initials: G
authors.lastname: Campanholle
authors.forename: Vanesa
authors.initials: V
authors.lastname: Bijol
authors.forename: Chang
authors.initials: C
authors.lastname: Wang
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Sabbisetti
authors.forename: Takaharu
authors.initials: T
authors.lastname: Ichimura
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Humphreys
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D005921:Glomerulonephritis / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012038:Regeneration; D013997:Time Factors
chemical_list: C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D049452:Green Fluorescent Proteins