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?Klotho Mitigates Progression of AKI to CKD through Activation of Autophagy.

ABSTRACT: AKI confers increased risk of progression to CKD. ?Klotho is a cytoprotective protein, the expression of which is reduced in AKI, but the relationship of ?Klotho expression level to AKI progression to CKD has not been studied. We altered systemic ?Klotho 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 ?Klotho-hypomorphic mice (?Klotho haploinsufficiency) progressed to CKD much faster, whereas ?Klotho-overexpressing mice had better preserved renal function after AKI. High phosphate diet exacerbated ?Klotho deficiency after AKI, dramatically increased renal fibrosis, and accelerated CKD progression. Recombinant ?Klotho administration after AKI accelerated renal recovery and reduced renal fibrosis. Compared with wild-type conditions, ?Klotho 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 ?Klotho upregulates autophagy, attenuates ischemic injury, mitigates renal fibrosis, and retards AKI progression to CKD.

SUBMITTER: Shi M

PROVIDER: S-EPMC4978045 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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αKlotho Mitigates Progression of AKI to CKD through Activation of Autophagy.

Shi Mingjun M Flores Brianna B Gillings Nancy N Bian Ao A Cho Han Jun HJ Yan Shirley S Liu Yang Y Levine Beth B Moe Orson W OW Hu Ming Chang MC

Journal of the American Society of Nephrology : JASN 20151223 8

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. De ...[more]

PMID: 26701976

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Project description:Background: Acute kidney injury (AKI) occurs in approximately 7-18% of all hospitalizations, but there are currently no effective drug therapy for preventing AKI or delaying its progression to chronic kidney disease (CKD). Recent studies have shown that Scutellaria baicalensis, a traditional Chinese herb, could attenuate cisplatin-induced AKI, although the mechanism remains elusive. Further, it is unknown whether its major active component, Oroxylin A (OA), can alleviate kidney injury. Methods: The therapeutic effect of OA was evaluated by using ischemia-reperfusion (IR) and cisplatin mediated-AKI mice and HK-2 cells under hypoxia-reoxygenation (HR) conditions. HE staining, transmission electron microscopy, flow cytometry, immunofluorescence, qPCR, Western blot, PPARα inhibitor, BNIP3 siRNA and ChIP assay were used to explore the role and mechanism of OA in AKI. Results: OA ameliorated tubular damage and dramatically decreased serum creatinine (Scr) and urea nitrogen (BUN), and the expressions of renal injury markers (Kim-1, Ngal) in AKI mice induced by both IR injury and cisplatin, as well as attenuating AKI-to-CKD transition. In vitro experiments showed that OA alleviated HR-induced mitochondrial homeostasis imbalance in renal tubular epithelial cells. Mechanistically, OA dose-dependently induced the expression of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), while knockdown of BNIP3 expression reversed the protection of OA against HR-mediated mitochondrial injury. Network pharmacological analysis and experimental validation suggested that OA enhanced BNIP3 expression via upregulating the expression of peroxisome proliferator activated receptor alpha (PPARα), which induced the transcription of BNIP3 via directly binding to its promoter region. Both in vitro and in vivo experiments confirmed that the renoprotective effect of OA was dramatically reduced by GW6471, a PPARα antagonist. Conclusion: Our findings revealed that OA ameliorates AKI-to-CKD transition by maintaining mitochondrial homeostasis through inducing PPARα-BNIP3 signaling pathway, indicating that OA may serve as a candidate therapeutic strategy for alleviating AKI and CKD.

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?Klotho Mitigates Progression of AKI to CKD through Activation of Autophagy.

Publications

αKlotho Mitigates Progression of AKI to CKD through Activation of Autophagy.

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