αKlotho Mitigates Progression of AKI to CKD through Activation of Autophagy

AKI confers increased risk of progression to CKD. alpha Klotho is a cytoprotective protein, the expression of which is reduced in AKI, but the relationship of alpha Klotho expression level to AKI progression to CKD has not been studied. We altered systemic alpha 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 alpha Klotho-hypomorphic mice (alpha Klotho haploinsufficiency) progressed to CKD much faster, whereas alpha Klotho-overexpressing mice had better preserved renal function after AKI. High phosphate diet exacerbated alpha Klotho deficiency after AKI, dramatically increased renal fibrosis, and accelerated CKD progression. Recombinant alpha Klotho administration after AKI accelerated renal recovery and reduced renal fibrosis. Compared with wild-type conditions, alpha 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 alpha Klotho upregulates autophagy, attenuates ischemic injury, mitigates renal fibrosis, and retards AKI progression to CKD.