Anserine and Carnosine Induce HSP70-Dependent H(2)S Formation in Endothelial Cells and Murine Kidney

Anserine and carnosine have nephroprotective actions; hydrogen sulfide (H(2)S) protects from ischemic tissue damage, and the underlying mechanisms are debated. In view of their common interaction with HSP70, we studied possible interactions of both dipeptides with H(2)S. H(2)S formation was measured in human proximal tubular epithelial cells (HK-2); three endothelial cell lines (HUVEC, HUAEC, MCEC); and in renal murine tissue of wild-type (WT), carnosinase-1 knockout (Cndp1-KO) and Hsp70-KO mice. Diabetes was induced by streptozocin. Incubation with carnosine increased H(2)S synthesis capacity in tubular cells, as well as with anserine in all three endothelial cell lines. H(2)S dose-dependently reduced anserine/carnosine degradation rate by serum and recombinant carnosinase-1 (CN1). Endothelial Hsp70-KO reduced H(2)S formation and abolished the stimulation by anserine and could be restored by Hsp70 transfection. In female Hsp70-KO mice, kidney H(2)S formation was halved. In Cndp1-KO mice, kidney anserine concentrations were several-fold and sex-specifically increased. Kidney H(2)S formation capacity was increased 2–3-fold in female mice and correlated with anserine and carnosine concentrations. In diabetic Cndp1-KO mice, renal anserine and carnosine concentrations as well as H(2)S formation capacity were markedly reduced compared to non-diabetic Cndp1-KO littermates. Anserine and carnosine induce H(2)S formation in a cell-type and Hsp70-specific manner within a positive feedback loop with CN1.