Klotho-derived peptide 6 (KP6) binds to Wnt ligands and disrupts the engagement of Wnts with low density lipoprotein receptor-related protein 6 (LRD6), interrupting Wnt/ beta-catenin signaling. Klotho, an anti-aging protein, is kidney protective in Diabetic kidney disease (DKD). In vitro, KP6 prevents podocyte injury and inhibits beta-catenin activation induced by high glucose without affecting Wnt expression. KP6 inhibits beta-catenin activation in vivo and blocks the expression of its downstream target genes in glomerular podocytes and tubular epithelial cells. In DKD animal models, chronic infusion of KP6 reverses established proteinuria, attenuates glomerular hypertrophy, mitigates podocyte damage, and ameliorates glomerulosclerosis and interstitial fibrotic lesions.
