| Summary: | Anserine and carnosine have nephroprotective actions; hydrogen sulfide (H<sub>2</sub>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<sub>2</sub>S. H<sub>2</sub>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 <i>(Cndp1</i>-KO) and <i>Hsp70</i>-KO mice. Diabetes was induced by streptozocin. Incubation with carnosine increased H<sub>2</sub>S synthesis capacity in tubular cells, as well as with anserine in all three endothelial cell lines. H<sub>2</sub>S dose-dependently reduced anserine/carnosine degradation rate by serum and recombinant carnosinase-1 (CN1). Endothelial <i>Hsp70</i>-KO reduced H<sub>2</sub>S formation and abolished the stimulation by anserine and could be restored by <i>Hsp70</i> transfection. In female <i>Hsp70</i>-KO mice, kidney H<sub>2</sub>S formation was halved. In <i>Cndp1</i>-KO mice, kidney anserine concentrations were several-fold and sex-specifically increased. Kidney H<sub>2</sub>S formation capacity was increased 2–3-fold in female mice and correlated with anserine and carnosine concentrations. In diabetic <i>Cndp1</i>-KO mice, renal anserine and carnosine concentrations as well as H<sub>2</sub>S formation capacity were markedly reduced compared to non-diabetic <i>Cndp1</i>-KO littermates. Anserine and carnosine induce H<sub>2</sub>S formation in a cell-type and Hsp70-specific manner within a positive feedback loop with CN1.
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