title: Severity and Frequency of Proximal Tubule Injury Determines Renal Prognosis.
abstract: AKI increases the risk of developing CKD, but the mechanisms linking AKI to CKD remain unclear. Because proximal tubule injury is the mainstay of AKI, we postulated that proximal tubule injury triggers features of CKD. We generated a novel mouse model to induce proximal tubule-specific adjustable injury by inducing the expression of diphtheria toxin (DT) receptor with variable prevalence in proximal tubules. Administration of high-dose DT in mice expressing the DT receptor consistently caused severe proximal tubule-specific injury associated with interstitial fibrosis and reduction of erythropoietin production. Mild proximal tubule injury from a single injection of low-dose DT triggered reversible fibrosis, whereas repeated mild injuries caused sustained interstitial fibrosis, inflammation, glomerulosclerosis, and atubular glomeruli. DT-induced proximal tubule-specific injury also triggered distal tubule injury. Furthermore, injured tubular cells cocultured with fibroblasts stimulated induction of extracellular matrix and inflammatory genes. These results support the existence of proximal-distal tubule crosstalk and crosstalk between tubular cells and fibroblasts. Overall, our data provide evidence that proximal tubule injury triggers several features of CKD and that the severity and frequency of proximal tubule injury determines the progression to CKD.
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Koji
authors.initials: K
authors.lastname: Takaori
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Jin
authors.initials: J
authors.lastname: Nakamura
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Nakata
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takase
authors.affiliation: Department of Structural Pathology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan;
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nameta
authors.affiliation: Department of Structural Pathology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan;
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Genome Engineering Technologies and Skeletal Diseases TFA Groups, Regeneron Pharmaceuticals, Inc., Tarrytown, New York;
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan;
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohno
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan; and.
authors.forename: Hironori
authors.initials: H
authors.lastname: Haga
authors.affiliation: Center for Renal Translational Medicine and Institute of Metabolomic Medicine, Department of Medicine, University of California San Diego, Veteran's Administration San Diego HealthCare System, La Jolla, California.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; motoy@kuhp.kyoto-u.ac.jp.
authors.forename: Motoko
authors.initials: M
authors.lastname: Yanagita
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications*; D000818:Animals; D018450:Disease Progression; D007687:Kidney Tubules, Proximal / Q000473:pathology; D051379:Mice; D011379:Prognosis; D051436:Renal Insufficiency, Chronic / Q000209:etiology*; D012720:Severity of Illness Index
keywords: acute renal failure; chronic kidney disease; proximal tubule