title: αKlotho Mitigates Progression of AKI to CKD through Activation of Autophagy.
abstract: AKI confers increased risk of progression to CKD. αKlotho is a cytoprotective protein, the expression of which is reduced in AKI, but the relationship of αKlotho expression level to AKI progression to CKD has not been studied. We altered systemic αKlotho levels by genetic manipulation, phosphate loading, or aging and examined the effect on long-term outcome after AKI in two models: bilateral ischemia-reperfusion injury and unilateral nephrectomy plus contralateral ischemia-reperfusion injury. Despite apparent initial complete recovery of renal function, both types of AKI eventually progressed to CKD, with decreased creatinine clearance, hyperphosphatemia, and renal fibrosis. Compared with wild-type mice, heterozygous αKlotho-hypomorphic mice (αKlotho haploinsufficiency) progressed to CKD much faster, whereas αKlotho-overexpressing mice had better preserved renal function after AKI. High phosphate diet exacerbated αKlotho deficiency after AKI, dramatically increased renal fibrosis, and accelerated CKD progression. Recombinant αKlotho administration after AKI accelerated renal recovery and reduced renal fibrosis. Compared with wild-type conditions, αKlotho deficiency and overexpression are associated with lower and higher autophagic flux in the kidney, respectively. Upregulation of autophagy protected kidney cells in culture from oxidative stress and reduced collagen 1 accumulation. We propose that αKlotho upregulates autophagy, attenuates ischemic injury, mitigates renal fibrosis, and retards AKI progression to CKD.
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Shi
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research.
authors.forename: Brianna
authors.initials: B
authors.lastname: Flores
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research.
authors.forename: Nancy
authors.initials: N
authors.lastname: Gillings
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research.
authors.forename: Ao
authors.initials: A
authors.lastname: Bian
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research.
authors.forename: Han Jun
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Departments of Pathology.
authors.forename: Shirley
authors.initials: S
authors.lastname: Yan
authors.affiliation: Internal Medicine, Center for Autophagy Research, and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Internal Medicine, Center for Autophagy Research, and Microbiology, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Internal Medicine, Physiology, orson.moe@utsouthwestern.edu ming-chang.hu@utsouthwestern.edu.
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Internal Medicine, orson.moe@utsouthwestern.edu ming-chang.hu@utsouthwestern.edu.
authors.forename: Ming Chang
authors.initials: MC
authors.lastname: Hu
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D018450:Disease Progression; D005966:Glucuronidase; D000090265:Klotho Proteins; D051379:Mice; D011956:Receptors, Cell Surface / Q000502:physiology* / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000209:etiology* / Q000517:prevention & control
chemical_list: D011956:Receptors, Cell Surface; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: acute kidney injury; autophagy; chronic kidney disease; ischemia-reperfusion injury; renal fibrosis; αKlotho