L-Carnosine alleviates cadmium induced disruption of K-Cadherin /Catenin/ Wnt signaling in human renal proximal tubule epithelial cells

Abstract

Introduction: Nephrotoxin cadmium (Cd) is a common environmental pollutant associated with
chronic kidney disease (CKD) characterized by interstitial fibrosis. Cadmium activates wnt/β catenin
signaling pathway while aberrant wnt activation is implicated in fibrosis. Dipeptide L-carnosine is
known to mitigate detrimental effects of metal compounds on mammalian cells.
Objectives: Objective was to demonstrate that L-carnosine is capable of alleviating activation of wnt/
β catenin signaling pathway induced by cadmium in human proximal tubule epithelial cells (PTEC’s)
that express K-cadherin.
Methods: Cultured PTEC’s were treated with either vehicle, 10μM of Cd, 50 mM of L-carnosine or a
combination of the latter two for 24h. Levels of K-cadherin in PTEC’s were evaluated with
immunoblotting. To study the activation of Wnt signaling pathway, PTEC’s were transfected with
TCF/LEF transcriptional response element linked to luciferase reporter gene and resultant luciferace
activity was measured by dual-luciferase reporter assay.
Results: Cadmium caused a significant reduction (p<0.05) in K-cadherin expression in PTEC’s which
was not observed in the presence of L-carnosine. Cadmium induced a marked activation (p<0.01) of
TCF/LEF-mediated gene transcription whereas in PTEC’s treated with Cd and L-carnosine, activation
was significantly less (p<0.01). L-Carnosine alone had minimal effect on TCF/LEF promoter activity.
Conclusions: Taken together these results are supportive of L-carnosine alleviating cadmium induced
loss of K-cadherin and activation of Wnt signaling pathway in PTEC’s. Protective effects of Lcarnosine
in PTEC’s raise its profile as a potential therapeutic agent in cadmium induced CKD.