| First Author | Shi M | Year | 2016 |
| Journal | J Am Soc Nephrol | Volume | 27 |
| Issue | 8 | Pages | 2331-45 |
| PubMed ID | 26701976 | Mgi Jnum | J:290891 |
| Mgi Id | MGI:6436959 | Doi | 10.1681/ASN.2015060613 |
| Citation | Shi M, et al. (2016) alphaKlotho Mitigates Progression of AKI to CKD through Activation of Autophagy. J Am Soc Nephrol 27(8):2331-45 |
| abstractText | AKI confers increased risk of progression to CKD. alphaKlotho is a cytoprotective protein, the expression of which is reduced in AKI, but the relationship of alphaKlotho expression level to AKI progression to CKD has not been studied. We altered systemic alphaKlotho 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 alphaKlotho-hypomorphic mice (alphaKlotho haploinsufficiency) progressed to CKD much faster, whereas alphaKlotho-overexpressing mice had better preserved renal function after AKI. High phosphate diet exacerbated alphaKlotho deficiency after AKI, dramatically increased renal fibrosis, and accelerated CKD progression. Recombinant alphaKlotho administration after AKI accelerated renal recovery and reduced renal fibrosis. Compared with wild-type conditions, alphaKlotho 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 alphaKlotho upregulates autophagy, attenuates ischemic injury, mitigates renal fibrosis, and retards AKI progression to CKD. |
