Abstract
Dysregulation of fatty acid oxidation and accumulation of fatty acids can cause kidney injury. Nifedipine modulates lipogenesis-related transcriptional factor SREBP-1/2 in proximal tubular cells by inhibiting the Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) pathway in vitro. However, the mechanisms by which nifedipine (NF) modulates lipotoxicity in vivo are unclear. Here, we examined the effect of NF in a doxorubicin (DR)-induced kidney injury rat model. Twenty-four Sprague–Dawley rats were divided into control, DR, DR+NF, and high-fat diet (HFD) groups. The DR, DR+NF, and HFD groups showed hypertension and proteinuria. Western blotting and immunohistochemical analysis showed that NF significantly induced TNF-α, CD36, SREBP-1/2, and acetyl-CoA carboxylase expression and renal fibrosis, and reduced fatty acid synthase and AMPK compared to other groups (p < 0.05). Additionally, 18 patients with chronic kidney disease (CKD) who received renal transplants were enrolled to examine their graft fibrosis and lipid contents via transient elastography. Low-density lipoprotein levels in patients with CKD strongly correlated with lipid contents and fibrosis in grafted kidneys (p < 0.05). Thus, NF may initiate lipogenesis through the SREBP-1/2/AMPK pathway and lipid uptake by CD36 upregulation and aggravate renal fibrosis in vivo. Higher low-density lipoprotein levels may correlate with renal fibrosis and lipid accumulation in grafted kidneys of patients with CKD.
Highlights
Lipid accumulation in kidney tissue [1,2] causes fatty kidney and lipotoxicity and may result in acute kidney injury, which further transforms into chronic kidney disease (CKD) and renal fibrosis [3]
The Sprague–Dawley rats used in this study were divided into four groups: control, doxorubicin (DR) (DR-induced kidney injury model fed standard chow), DR+NF (DR-induced kidney injury model fed standard chow plus NF), and high-fat diet (HFD) groups
Renal injury was successfully established in the DR and HFD groups, as demonstrated by complications including high proteinuria and blood pressure, observed starting at week 3
Summary
Lipid accumulation in kidney tissue [1,2] causes fatty kidney and lipotoxicity and may result in acute kidney injury, which further transforms into chronic kidney disease (CKD) and renal fibrosis [3]. Reports show that both the impairment of fatty acid oxidation and ATP depletion contribute to renal fibrosis [6]. Reduced activity of AMP-activated protein kinase (AMPK), an energy-sensing molecule that is abundant in mitochondria of the renal tubule and utilizes fatty acids as ATP sources through oxidation, may contribute to lipogenesis [9,10]. Alleviating renal lipotoxicity via regulation of endothelial fatty acid transcytosis, according to a study of a diabetic kidney disease mouse model, may prevent renal dysfunction [11]
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