αklotho mitigates progression of aki to ckd through activation of autophagy

Mingjun Shi, Brianna Flores, Nancy Gillings, Ao Bian, Han Jun Cho, Shirley X Yan, Yang Liu, Beth Levine, Orson W Moe, Ming C Hu

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 fromoxidative stress and reduced collagen 1 accumulation.We propose thatαKlotho upregulates autophagy, attenuates ischemic injury, mitigates renal fibrosis, and retards AKI progression to CKD.

Original languageEnglish (US)
Pages (from-to)2331-2345
Number of pages15
JournalJournal of the American Society of Nephrology
Volume27
Issue number8
DOIs
StatePublished - 2016

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Autophagy
Kidney
Fibrosis
Reperfusion Injury
Up-Regulation
Phosphates
Hyperphosphatemia
Haploinsufficiency
Recovery of Function
Nephrectomy
Creatinine
Collagen
Cell Culture Techniques
Diet
Wounds and Injuries

ASJC Scopus subject areas

  • Nephrology

Cite this

αklotho mitigates progression of aki to ckd through activation of autophagy. / Shi, Mingjun; Flores, Brianna; Gillings, Nancy; Bian, Ao; Cho, Han Jun; Yan, Shirley X; Liu, Yang; Levine, Beth; Moe, Orson W; Hu, Ming C.

In: Journal of the American Society of Nephrology, Vol. 27, No. 8, 2016, p. 2331-2345.

Research output: Contribution to journalArticle

Shi, Mingjun ; Flores, Brianna ; Gillings, Nancy ; Bian, Ao ; Cho, Han Jun ; Yan, Shirley X ; Liu, Yang ; Levine, Beth ; Moe, Orson W ; Hu, Ming C. / αklotho mitigates progression of aki to ckd through activation of autophagy. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 8. pp. 2331-2345.
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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 fromoxidative stress and reduced collagen 1 accumulation.We propose thatαKlotho upregulates autophagy, attenuates ischemic injury, mitigates renal fibrosis, and retards AKI progression to CKD.",
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