αKlotho Mitigates Progression of AKI to CKD through Activation of Autophagy.
Journal: 2017/May - Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
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.
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J Am Soc Nephrol 27(8): 2331-2345

<em>α</em>Klotho Mitigates Progression of AKI to CKD through Activation of Autophagy

Supplementary Material

Supplemental Data:
Charles and Jane Pak Center for Mineral Metabolism and Clinical Research,
Departments of Pathology,
Internal Medicine,
Microbiology, and
Physiology,
Center for Autophagy Research, and
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas
Corresponding author.
Present address: Dr. Ao Bian, Department of Internal Medicine, Division of Nephrology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Correspondence: Dr. Orson W. Moe or Dr. Ming Chang Hu, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8885. Email: ude.nretsewhtuostu@eom.nosro or ude.nretsewhtuostu@uh.gnahc-gnim
Received 2015 Jun 3; Accepted 2015 Nov 1.

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.

Keywords: acute kidney injury, chronic kidney disease, autophagy, renal fibrosis, ischemia-reperfusion injury, αKlotho
Abstract

AKI confers formidable morbidity and mortality in its acute phase, especially in the intensive care unit setting, where mortality is as high as 50%.1,2 Among survivors of AKI, the long-term outcome is far from benign. Patients who recover from AKI have a 25% increase in risk for CKD and a 50% increase in mortality after follow-up of approximately 10 years.3,4 Although clinical observations describe a clear association, they do not establish a causal link between AKI and CKD; human data from longitudinal post–AKI cohorts will be required but will take many years to obtain. As an initial exploration of this paradigm, we used rodent AKI models to examine CKD progression post-AKI with emphasis on the role of αKlotho post-AKI.

Klotho was initially discovered as an antiaging protein5 and is now called αKlotho to distinguish it from two other paralogs: βKlotho6 and γKlotho.7αKlotho is a type 1 transmembrane protein highly expressed in the kidney and brain.8 The extracellular domain of transmembrane αKlotho can be released into the circulation as soluble αKlotho by secretases912 and functions as an endocrine factor to exert a myriad of biologic effects on multiple target organs.13,14αKlotho is involved in cytoprotection, antiapoptosis, anticell senescence, and antifibrosis, all of which may be crucial in tissue protection and regeneration.15,16 Animal studies have shown that (1) AKI from ischemic injury and AKI from cisplatin nephrotoxicity are transient states of αKlotho deficiency,17,18 (2) αKlotho protects the kidney from ischemic AKI when given immediately after the insult,18 and (3) restoration of αKlotho after established unilateral ureteral obstruction can prevent subsequent renal fibrosis.19,20 Clinical observational studies have shown αKlotho deficiency in both AKI18 and CKD.15,21,22 The relationship between αKlotho deficiency and CKD progression post-AKI has not been examined. This is a critical but unexplored pathophysiologic mechanism with immense therapeutic potential.

Autophagy is an evolutionarily conserved catabolic process for lysosomal degradation or recycling of cytoplasmic components and serves as a defense mechanism to protect and maintain normal cellular function.2325 Defective or excessive autophagic flux contributes to aging and various diseases in humans.25,26 In ischemia-27,28 or cisplatin-induced2933 AKI and unilateral ureteral obstruction,34,35 autophagy is activated. Several lines of evidence in animals showed that defective autophagy renders the kidney vulnerable to ischemic injury and nephrotoxicity.2934,36,37 Dysfunction in autophagy also contributes to aging in all organs and tissues.3840 Associations between the levels of autophagy and αKlotho have previously been reported, but the results were not consistent.4144 Furthermore, whether the renoprotection rendered by αKlotho is related to modulation of autophagy has not been studied.

There were several objectives in this study. First, we strived to define appropriate AKI models that spontaneously and reliably progress to CKD. Second, we examined whether renal αKlotho deficiency is associated with CKD development post-AKI, and we manipulated endogenous αKlotho levels to examine whether its deficiency has a causal role in CKD. Third, we sought to define the therapeutic effect of αKlotho on the blockage of AKI progression to CKD. Fourth, we explored whether changes in αKlotho levels are associated with and alter levels of autophagy, cytoprotection, and extracellular matrix accumulation. Our studies establish a novel mechanistic link between αKlotho, autophagy, and renoprotection against fibrosis and post-AKI progression to CKD. We propose that the αKlotho deficiency leads to insufficient autophagy and renders the kidney more vulnerable to ischemic injury and that αKlotho administration post-AKI is a potential therapeutic agent for promotion of kidney recovery, suppression of renal fibrosis post-AKI, and prevention of progression to CKD.

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Acknowledgments

The authors thank Dr. Makoto Kuro-o for continuous helpful discussions and provision of reagents. The authors thank Dr. Noboru Mizushima (Tokyo Medical and Dental University) for providing the transgenic GFP-LC3 reporter mouse and the GFP-LC3 plasmid and Dr. Joseph Hill (University of Texas Southwestern Medical Center) for providing the transgenic RFP;GFP-LC3 reporter mouse. The authors also thank Ms. Jean Paek and Ms. Jessica Lucas for technical assistance.

The authors were, in part, supported by National Institutes of Health Grants R01-DK091392 and R01-DK092461, George M. O’Brien Kidney Research Center Grant P30-DK-07938, the Simmons Family Foundation, the Pak Center Innovative Research Support Program, and the Pak-Seldin Center for Metabolic and Clinical Research.

Acknowledgments

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2015060613/-/DCSupplemental.

Footnotes

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