Abstract
Prolyl hydroxylase (PH) enzymes control the degradation of hypoxia-inducible factor (HIF), a transcription factor known to regulate erythropoiesis, angiogenesis, glucose metabolism, cell proliferation, and apoptosis. HIF-PH inhibitors (HIF-PHIs) correct anemia in patients with renal disease and in animal models of anemia and kidney disease. However, the effects of HIF-PHIs on comorbidities associated with kidney disease remain largely unknown. We evaluated the effects of the HIF-PHI FG-2216 in obese ZSF1 (Ob-ZSF1) rats, an established model of kidney failure with metabolic syndrome. Following unilateral nephrectomy (Nx) at 8 weeks of age, rats were treated with 40 mg/kg FG-2216 or vehicle by oral gavage three times per week for up to 18 weeks. FG-2216 corrected blood hemoglobin levels and improved kidney function and histopathology in Nx-Ob-ZSF1 rats by increasing the glomerular filtration rate, decreasing proteinuria, and reducing peritubular fibrosis, tubular damage, glomerulosclerosis and mesangial expansion. FG-2216 increased renal glucose excretion and decreased body weight, fat pad weight, and serum cholesterol in Nx-Ob-ZSF1 rats. Additionally, FG-2216 corrected hypertension, improved diastolic and systolic heart function, and reduced cardiac hypertrophy and fibrosis. In conclusion, the HIF-PHI FG-2216 improved renal and cardiovascular outcomes, and reduced obesity in a rat model of kidney disease with metabolic syndrome. Thus, in addition to correcting anemia, HIF-PHIs may provide renal and cardiac protection to patients suffering from kidney disease with metabolic syndrome.
Highlights
Chronic kidney disease (CKD) is a major challenge in public health, affecting an estimated 15% of people in the United States and more than 11% worldwide [1, 2]
Before FG-2216 treatment, baseline parameters were determined for lean ZSF1 rats that underwent a sham procedure (Ln-ZSF1) and obese ZSF1 rats that underwent unilateral nephrectomy (Nx) to accelerate the development of nephropathy (Nx-Ob-ZSF1)
Nephrectomy of the left kidneys resulted in significantly larger right kidneys in both Nx-Ob-ZSF1 Vehicle and Nx-Ob-ZSF1 FG-2216 rats than in nonnephrectomized Ln-ZSF1 rats (Fig 4I). These results show that FG-2216 improved kidney histopathology by decreasing tubular interstitial fibrosis, tubular damage, mesangial expansion and glomerulosclerosis in Nx-Ob-ZSF1 rats
Summary
Chronic kidney disease (CKD) is a major challenge in public health, affecting an estimated 15% of people in the United States and more than 11% worldwide [1, 2]. CKD is associated with several comorbidities, including hypertension, heart failure, diabetes, obesity, and hyperlipidemia [3,4,5]. Anemia is a common complication of renal disease because failing kidneys do not produce enough erythropoietin (EPO) to maintain normal levels of red blood cells, and the liver cannot fully compensate by secreting its own EPO [6]. HIF-PHI improves obesity, nephropathy and cardiomyopathy specific roles of these authors are articulated in the ‘author contributions’ section
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