Endogenous HS production deficiencies lead to impaired renal erythropoietin production.

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 (H2S), an endogenously derived renal oxygen sensor. Previous in vitro experiments have revealed that H2S-deficient renal cell lines produce less EPO than wild-type renal cell lines during hypoxia. Methods: We postulated that H2S 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% O-2), partial H2S knockout mice (lacking the H2S biosynthetic enzyme cystathionine gamma-lyase [CSE]) displayed lower levels of hemoglobin, EPO, and cystathionine-beta-synthase (CBS) (another H2S biosynthetic enzyme) compared to wild-type mice, all of which was rescued by exogenous H2S 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 H2S during hypoxia and EPO production.