Steatosis is involved in the progression of kidney disease in a high-fat-diet-induced non-alcoholic steatohepatitis mouse model

Abstract

Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health issues associated with the metabolic syndrome. Although NASH is a known risk factor of CKD, the mechanisms linking these two diseases remain poorly understood. We aimed to investigate alterations in the kidney complicated with dyslipidemia in an established NASH mouse model. Male C57BL6/J mice were fed with control diet or high-fat diet (HFD), containing 40% fat, 22% fructose, and 2% cholesterol for 16 weeks. Metabolic characteristics, histological changes in the kidney, endoplasmic reticulum (ER) stress, apoptosis, and fibrosis were evaluated by histological analysis, immunoblotting, and quantitative reverse transcription-polymerase chain reaction. Levels of serum aspartate aminotransferase, alanine aminotransferase, alkali-phosphatase, total cholesterol, and urinary albumin were significantly higher in mice fed with HFD. Remarkable steatosis, glomerular hypertrophy, and interstitial fibrosis were also shown in in the kidney by leveraging HFD. Furthermore, HFD increased the mRNA expression levels of Casp3, Tgfb1, and Nfe2l2 and the protein level of BiP. We observed the early changes of CKD and speculate that the underlying mechanisms that link CKD and NASH are the induction of ER stress and apoptosis. Further, we observed the activation of Nfe2l2 in the steatosis-induced CKD mouse model. This NASH model holds implications in investigating the mechanisms linking dyslipidemia and CKD.

Five-Aminolevulinic Acid (5-ALA) Induces Heme Oxygenase-1 and Ameliorates Palmitic Acid-Induced Endoplasmic Reticulum Stress in Renal Tubules

“…Cardiac steatosis and cardiomyopathy have been observed in mice fed a high-fat diet [ 25 ]. We previously reported that a high-fat diet induced renal tubular steatosis and renal dysfunction in C57BL/6 mice and fatty liver Shionogi- ob/ob , genetically modified mice exhibiting the NASH phenotype [ 13 , 14 ]. These associations between dysregulated lipid metabolism and multiple-organ steatosis suggest a common underlying pathophysiology of NASH, cardiomyopathy, and steatonephropathy.…”

“…Endoplasmic reticulum (ER) stress, induced by steatosis or ectopic lipid deposition in hepatocytes, is one such mechanism associated with NASH pathophysiology [ 11 , 12 ]. Similar to the liver, steatosis in renal tubules is closely associated with kidney injury via the induction of ER stress [ 13 , 14 ]. Therefore, ER stress could be a therapeutic target to protect the kidneys against lipotoxicity.…”

Effect of (poly)phenol-rich ‘Daux Belan’ apple supplementation on diet-induced obesity and glucose intolerance in C57BL/6NCrl mice

“…As such, considering these factors that influence DIO susceptibility, potential counteracting approaches can include repeating the study in multiple cohorts of animals to deliver greater insights and distinguishing between HF-tolerant and intolerant animals, which can be accomplished by increasing the number of animals to offset variability while maintaining statistical power or by performing a median-based split on food intake data 32 . Additional blood parameters (total cholesterol and total protein) 33 , hepatic health parameters (aspartate aminotransferase and alanine aminotransferase activity) 33 , and organ weights (kidney and fat pad) 34 can be determined in future studies to increase resolution of the metabolic impact of HF-feeding and apple powder supplementation. Moreover, whole apple supplementation has been found to reduce flavan-3-ols bioaccessibility and thus its serum concentration in minipigs when compared with extract supplementation 35 .…”

Neutrophils and NADPH Oxidases Are Major Contributors to Mild but Not Severe Ischemic Acute Kidney Injury in Mice

“…Expression levels were quantified by a Bio-Rad C1000™ Thermal Cycler with CFX96™ Optics Module real-time PCR system (Bio-Rad Laboratories, Inc., Singapore), using primer sequences from IDT ( Table 1 ). Primers were designed by NCBI/Primer-BLAST online, except for the Gpx3 primer, adapted from Li et al [ 41 ], and for the NRF2 primer, adapted from Hamada et al [ 53 ]. All samples were measured in duplicates and mRNA expression was calculated using the relative quantification (ΔΔCq) method.…”