Background: Osteoporosis is a very common skeletal disorder that increases the risk of fractures. However, the treatment of osteoporosis is challenging. Hypoxia-inducible factor-1α (HIF-1α) plays an important role in bone metabolism. Roxadustat is a novel HIF stabilizer, and its effects on bone metabolism remain unknown. This study aimed to investigate the effects of roxadustat on osteoblast differentiation and bone remodeling in an ovariectomized (OVX) rat model. Methods: In vitro, primary mouse calvarial osteoblasts were treated with roxadustat. Alkaline phosphatase (ALP) activity and extracellular matrix mineralization were assessed. The mRNA and protein expression levels of osteogenic markers were detected. The effects of roxadustat on the HIF-1α and Wnt/β-catenin pathways were evaluated. Furthermore, osteoblast differentiation was assessed again after HIF-1α expression knockdown or inhibition of the Wnt/β-catenin pathway. In vivo, roxadustat was administered orally to OVX rats for 12 weeks. Then, bone histomorphometric analysis was performed. The protein expression levels of the osteogenic markers HIF-1α and β-catenin in bone tissue were detected. Results: In vitro, roxadustat significantly increased ALP staining intensity, enhanced matrix mineralization and upregulated the expression of osteogenic markers at the mRNA and protein levels in osteoblasts compared with the control group. Roxadustat activated the HIF-1α and Wnt/β-catenin pathways. HIF-1α knockdown or Wnt/β-catenin pathway inhibition significantly attenuated roxadustat-promoted osteoblast differentiation. In vivo, roxadustat administration improved bone microarchitecture deterioration and alleviated bone loss in OVX rats by promoting bone formation and inhibiting bone resorption. Roxadustat upregulated the protein expression levels of the osteogenic markers, HIF-1α and β-catenin in the bone tissue of OVX rats. Conclusion: Roxadustat promoted osteoblast differentiation and prevented bone loss in OVX rats. The use of roxadustat may be a new promising strategy to treat osteoporosis.

Background: Patients with kidney disease may have concurrent hypertension and infection. Dihydropyridine calcium-channel blockers (CCB) are the most popular class of antihypertensive drugs used in clinical settings and can be metabolized by cytochrome P450 isoenzyme 3A4 (CYP3A4). Voriconazole is a commonly used antifungal treatment and a CYP3A4-inhibitor. Insufficient attention to drug interactions from the concomitant use of CCB and voriconazole may result in serious adverse reactions. Case presentation: Here, we report a patient with acute kidney injury on stable anti-neutrophil cytoplasm antibody associated vasculitis who developed hyperkalemia resulting in sinus arrest with junctional escape rhythm attributed to drug interactions of CCB with voriconazole. This is a very rarely reported case and may be an under-recognized complication. After continuous renal replacement therapy and changing the anti-hypertensive drugs, symptoms, and laboratory abnormalities of the patient fully recovered. Conclusions: This case warns us of severe consequences of drug interactions. Co-prescription of CYP3A4-inhibitors with calcium-channel blockers increases the risk of hypotension and acute kidney injury, which may further induce hyperkalemia and arrhythmia.

Introduction: Cardiovascular disease represents the leading cause of mortality among patients with chronic kidney disease (CKD). CKD-associated cardiomyopathy is characterized by pathological left ventricular hypertrophy and myocardial fibrosis. Pegmolesatide, a novel pegylated continuous erythropoietin receptor activator, has demonstrated efficacy in treating renal anemia. However, the biological effects of Pegmolesatide beyond erythropoiesis remain poorly characterized. Methods: This study established a 5/6 nephrectomy rat model of CKD. The animals were randomized into four groups: sham-operated (Sham), sham-operated plus Pegmolesatide (Sham + Pegmolesatide), CKD model (CKD), and CKD model plus Pegmolesatide (CKD + Pegmolesatide). Cardiac function was assessed by echocardiography, while histopathological examination evaluated cardiac and renal structural changes. Serum renal function parameters were measured using biochemical assays. Myocardial expression of proteins and mRNAs related to fibrosis, hypertrophy, and associated signaling pathways was analyzed by Western blot and quantitative PCR. Furthermore, transcriptomic sequencing of myocardial tissue was performed, and in vitro experiments were conducted using AC16 human cardiomyocytes stimulated with serum from stage 5 CKD patients. Results: Transcriptomic sequencing suggested that the cardioprotective effects of Pegmolesatide might be associated with improved mitochondrial function and modulation of the STAT3 signaling pathway. Results demonstrated that Pegmolesatide significantly improved cardiac functional parameters and attenuated both myocardial fibrosis and cardiomyocyte hypertrophy. Mechanistic investigations revealed that these cardioprotective effects were mediated through inhibition of JAK2/STAT3 signaling pathway activation and concomitant improvement of mitochondrial function. Discussion: These findings demonstrate that pegmolesatide exerts anti-anemic effect-independent cardioprotection, offering novel insights into treating CKD-associated cardiomyopathy.