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 (HS), an endogenously derived renal oxygen sensor. Previous in vitro experiments have revealed that HS-deficient renal cell lines produce less EPO than wild-type renal cell lines during hypoxia.

Methods: We postulated that HS 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), partial HS knockout mice (lacking the HS biosynthetic enzyme cystathionine γ-lyase [CSE]) displayed lower levels of hemoglobin, EPO and cystathionine-β-synthase (CBS) (another HS 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 HS during hypoxia and EPO production.