Endogenous H2S production deficiencies lead to impaired renal erythropoietin production

摘要

Introduction Patients suffering from chronic kidney disease (CKD) experience a number of associated comorbidities, including anemia. Relative deficiency in renal erythropoietin (EPO) production is thought to be a primary cause of anemia. Interestingly, CKD patients display low levels of hydrogen sulfide (Hsub2/subS), an endogenously derived renal oxygen sensor. Previous in vitro experiments have revealed that Hsub2/subS-deficient renal cell lines produce less EPO than wild-type renal cell lines during hypoxia. Methods We postulated that Hsub2/subS might be a primary mediator of EPO synthesis during hypoxia, which was tested using an in vivo murine model of whole-body hypoxia and in clinical samples obtained from CKD patients. Results Following a 72-hour period of hypoxia (11% Osub2/sub), partial Hsub2/subS knockout mice (lacking the Hsub2/subS biosynthetic enzyme cystathionine γ-lyase [CSE]) displayed lower levels of hemoglobin, EPO, and cystathionine-β-synthase (CBS) (another Hsub2/subS biosynthetic enzyme) compared to wild-type mice, all of which was rescued by exogenous Hsub2/subS supplementation. We also found that anemic CKD patients requiring exogenous EPO exhibited lower urinary thiosulfate levels compared to non-anemic CKD patients of similar CKD classification. Conclusions Together, our results confirm an interplay between the actions of Hsub2/subS during hypoxia and EPO production.