Wetzel Charlotte, Pfeffer Tilman, Bulkescher Ruben, Zemva Johanna, Modafferi Sergio, Polimeni Alessandra, Salinaro Angela Trovato, Calabrese Vittorio, Schmitt Claus Peter, Peters Verena
Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, 69120 Heidelberg, Germany.
Antioxidants (Basel). 2022 Dec 28;12(1):66. doi: 10.3390/antiox12010066.
Anserine and carnosine have nephroprotective actions; hydrogen sulfide (HS) 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 HS. HS 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 -KO) and -KO mice. Diabetes was induced by streptozocin. Incubation with carnosine increased HS synthesis capacity in tubular cells, as well as with anserine in all three endothelial cell lines. HS dose-dependently reduced anserine/carnosine degradation rate by serum and recombinant carnosinase-1 (CN1). Endothelial -KO reduced HS formation and abolished the stimulation by anserine and could be restored by transfection. In female -KO mice, kidney HS formation was halved. In -KO mice, kidney anserine concentrations were several-fold and sex-specifically increased. Kidney HS formation capacity was increased 2-3-fold in female mice and correlated with anserine and carnosine concentrations. In diabetic -KO mice, renal anserine and carnosine concentrations as well as HS formation capacity were markedly reduced compared to non-diabetic -KO littermates. Anserine and carnosine induce HS formation in a cell-type and Hsp70-specific manner within a positive feedback loop with CN1.
鹅肌肽和肌肽具有肾脏保护作用；硫化氢（HS）可保护组织免受缺血性损伤，但其潜在机制仍存在争议。鉴于它们与热休克蛋白70（HSP70）的共同相互作用，我们研究了这两种二肽与HS之间可能的相互作用。在人近端肾小管上皮细胞（HK-2）、三种内皮细胞系（人脐静脉内皮细胞、人脐动脉内皮细胞、小鼠脑微血管内皮细胞）以及野生型（WT）、肌肽酶-1基因敲除（-KO）和双敲除小鼠的肾脏组织中测量了HS的生成。通过链脲佐菌素诱导糖尿病。用肌肽孵育可增加肾小管细胞中HS的合成能力，在所有三种内皮细胞系中用鹅肌肽孵育也有同样效果。HS剂量依赖性地降低了血清和重组肌肽酶-1（CN1）对鹅肌肽/肌肽的降解率。内皮细胞系-KO降低了HS的生成，并消除了鹅肌肽的刺激作用，转染可使其恢复。在雌性-KO小鼠中，肾脏HS生成减半。在-KO小鼠中，肾脏鹅肌肽浓度呈性别特异性地增加了几倍。雌性小鼠的肾脏HS生成能力增加了2至3倍，且与鹅肌肽和肌肽浓度相关。与非糖尿病-KO同窝小鼠相比，糖尿病-KO小鼠的肾脏鹅肌肽和肌肽浓度以及HS生成能力明显降低。鹅肌肽和肌肽在与CN1的正反馈回路中以细胞类型和Hsp70特异性的方式诱导HS生成。
