Inhibition of Endogenous Hydrogen Sulphide Production Decreases Hypoxia Induced Erythropoietin Release: Implications in End Stage Renal Disease.
Bibliographic record
Abstract
INTRODUCTION AND OBJECTIVES: Anemia of end stage renal disease (ESRD) affects over 90% of all hemodialysis patients and is a tremendous concern both for patients and health care providers. Natural erythropoietin (EPO) production is stimulated by local hypoxic conditions within the kidney tubular cells. Unfortunately over time, patients require exogenous EPO stimulating agents to treat their anemia, however they can become resistant to these agents thus necessitating increasing doses with resultant greater side effects. Novel therapeutics to overcome anemia of ESRD are necessary. Recent evidence suggests that endogenously produced hydrogen sulfide (H2S) may act as an oxygen sensor. Given the known involvement of other small molecules such as nitric oxide (NO) in natural EPO production and the observation of diminished urinary H2S levels in ESRD patients on hemodialysis, we postulated that H2S may be the primary mediator of EPO production during hypoxic conditions. METHODS: Hep3B cells are a well described model for EPO production. These cells were incubated under hypoxic conditions (1% O2) for 24 hours at 37°C. During hypoxia cells were treated with varying concentrations of the H2S donor, GYY 4137, the substrate for H2S biosynthesis, L-cysteine, and various inhibitors of H2S production, including DL-propargylglycine (PAG) and hydroxylamine (HA). RNA was collected following the end of hypoxia and EPO expression was measured by real time RT-PCR. RESULTS: In comparison to normoxic conditions, cells subjected to hypoxic conditions showed a significant increase in erythropoietin expression. Upon inhibiting endogenous H2S production using either HA and PAG, we found a significant decreases in EPO expression (p=0.013). Subsequent administration of GYY 4137 (500 uM) rescued the effect of these inhibitors, inducing a significant increase in EPO mRNA expression (p= 0.0012) compared to normoxic controls. CONCLUSIONS: These data are the first to show a novel influence of endogenous H2S on EPO production under hypoxic conditions. The use of novel oral H2S donors may represent a more efficacious and cost-effective alternative to expensive standard therapies in treatment of anemia of ESRD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".