Dataset Information

?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:Purpose: Acute kidney injury (AKI) is a prominent risk factor for the development of chronic kidney disease (CKD). To date, the related mechanism and effective therapy have not been rigorously explored. The present study aims to investigate the reno-protection of hydrogen-rich saline (HRS) against ischemia/reperfusion (IR)-induced AKI. Methods: Adult male C57 mice were randomly allocated into three groups: Sham, IR, IR+HRS. Renal IR injury model was generated via 35 min occlusion of bilateral kidney pedicles, and then, mice were administered with different treatments intraperitoneally in various groups. After 14- or 28-day treatment, mice were perfused and the kidneys were collected following reperfusion. Many proteins were detected by western blots, including renal fibrotic proteins [a-smooth muscle actin (a-SMA), collagen I (Col I)], Klotho, the methylation of Klotho, damage-regulated autophagy modulator (Beclin-1), and microtubule-associated protein light 3-II (LC3-II). Finally, the levels of serum blood urea nitrogen (BUN) and creatinine (Cr) were measured to investigate the renal function. Results: Histological data showed that the HRS treatment significantly decreased the fibrosis in renal tissues when compared with the IR group, and both of BUN and Cr were lower in the HRS group than IR group (8.9 ± 0.6 vs. 9.9 ± 0.1 mmol/l, 51 ± 6.5 vs. 60 ± 5.8 ?mol/l) (P < 0.05). The expression of fibrotic markers, a-SMA and Col I, showed a robust increase in IR injury models than the Sham group, which was consistent with the result of Trichrome staining. However, the levels of a-SMA and Col I expression were sharply decreased in the IR+HRS group (P < 0.05). IR injury also enhanced LC3-II and Beclin-1 expression, but decreased Klotho level. The Klotho level was alleviated by HRS, but LC3-II and Beclin-1 were starkly enhanced in HRS group (P < 0.05). Conclusion: HRS showed a protective effect in the prevention of renal injury and could inhibit renal fibrosis after IR injury in mice. This role of HRS might be exerted via retaining Klotho expression and activating autophagy in the kidney.

Dataset Information

?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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