αKlotho Mitigates Progression of AKI to CKD through Activation of Autophagy

• Published in: Journal of the American Society of Nephrology 2016-08, Vol.27 (8), p.2331-2345
• Main Authors: Shi, Mingjun, Flores, Brianna, Gillings, Nancy, Bian, Ao, Cho, Han Jun, Yan, Shirley, Liu, Yang, Levine, Beth, Moe, Orson W, Hu, Ming Chang
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - complications; Animals; Autophagy - drug effects; Autophagy - physiology; Basic Research; Disease Progression; Mice; Receptors, Cell Surface - physiology; Receptors, Cell Surface - therapeutic use; Renal Insufficiency, Chronic - etiology; Renal Insufficiency, Chronic - prevention & control
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2015060613

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.