Abstract
BackgroundPatients with salt-sensitive hypertension are often accompanied with severe renal damage and accelerate to end-stage renal disease, which currently lacks effective treatment. Fibroblast growth factor 21 (FGF21) has been shown to suppress nephropathy in both type 1 and type 2 diabetes mice. Here, we aimed to investigate the therapeutic effect of FGF21 in salt-sensitive hypertension-induced nephropathy.MethodsChanges of FGF21 expression in deoxycorticosterone acetate (DOCA)-salt-induced hypertensive mice were detected. The influence of FGF21 knockout in mice on DOCA-salt-induced nephropathy were determined. Recombinant human FGF21 (rhFGF21) was intraperitoneally injected into DOCA-salt-induced nephropathy mice, and then the inflammatory factors, oxidative stress levels and kidney injury-related indicators were observed. In vitro, human renal tubular epithelial cells (HK-2) were challenged by palmitate acid (PA) with or without FGF21, and then changes in inflammation and oxidative stress indicators were tested.ResultsWe observed significant elevation in circulating levels and renal expression of FGF21 in DOCA-salt-induced hypertensive mice. We found that deletion of FGF21 in mice aggravated DOCA-salt-induced nephropathy. Supplementation with rhFGF21 reversed DOCA-salt-induced kidney injury. Mechanically, rhFGF21 induced AMPK activation in DOCA-salt-treated mice and PA-stimulated HK-2 cells, which inhibited NF-κB-regulated inflammation and Nrf2-mediated oxidative stress and thus, is important for rhFGF21 protection against DOCA-salt-induced nephropathy.ConclusionThese findings indicated that rhFGF21 could be a promising pharmacological strategy for the treatment of salt-sensitive hypertension-induced nephropathy.
Highlights
Hypertension is an imbalance in the regulation of normal blood pressure caused by the interaction of polygenetic inheritance and multiple environmental factors, which has become a serious public health problem affecting 30% of adults around the world (Fatani et al 2021; YamamotoHanada et al 2021)
Circulating levels and renal expression of Fibroblast growth factor 21 (FGF21) in mice are largely increased in deoxycorticosterone acetate (DOCA)‐salt‐induced hypertensive renal damage To determine the successful establishment of a mouse model of salt-sensitive hypertensive nephropathy, the blood pressure, urinary albumin and urinary albumin/creatinine ratio were preliminarily evaluated
To explore the relationship between FGF21 and salt-sensitive hypertensive nephropathy, we investigated the changes of circulating FGF21 levels and its renal expression after treated with DOCA-salt for 8 days in mice
Summary
Hypertension is an imbalance in the regulation of normal blood pressure caused by the interaction of polygenetic inheritance and multiple environmental factors, which has become a serious public health problem affecting 30% of adults around the world (Fatani et al 2021; YamamotoHanada et al 2021). About 60% of patients with hypertension are sensitive to salt accompanied with uncontrollable blood pressure and serious complications (Rust and Ekmekcioglu 2017). Hypertension is the main risk factor for chronic kidney disease and one of the most common causes of renal failure (Gargiulo et al 2015). Studies have shown that patients with salt-sensitive hypertension tend to have more severe kidney damage and a higher rate of development of end-stage kidney disease (Slagman et al 2012). The molecular mechanism of the etiology of salt-sensitive hypertensive nephropathy (SSHN) is not clear and no effective treatment has been developed. Patients with salt-sensitive hypertension are often accompanied with severe renal damage and accelerate to end-stage renal disease, which currently lacks effective treatment. We aimed to investigate the therapeutic effect of FGF21 in salt-sensitive hypertension-induced nephropathy
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