期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1870, 期 1, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2023.166825
关键词
Chronic kidney disease; 8-Dihydroxyadenine nephropathy; mTOR; Endoplasmic reticulum stress; Mitochondrial function; Hexosylceramides
In mice, 2,8-dihydroxyadenine-induced chronic kidney disease (CKD) leads to renal activation of mTOR downstream signaling, endoplasmic reticulum stress, tubular injury, fibrosis, inflammation, oxidative stress, and impaired kidney mitochondrial function, accompanied by renal hexosylceramide accumulation.
Aim: Chronic kidney disease (CKD) is accompanied by increased cardiovascular risk and heart failure (HF). In rodents, 2,8-dihydroxyadenine (DHA)-induced nephropathy is a frequently used CKD model. Cardiac and kidney tubular cells share high energy demand to guarantee constant contractive force of the heart or reabsorption/ secretion of primary filtrated molecules and waste products by the kidney. Here we analyze time-dependent mechanisms of kidney damage and cardiac consequences under consideration of energetic pathways with the focus on mitochondrial function and lipid metabolism in mice.Methods and results: CKD was induced by alternating dietary adenine supplementation (0.2 % or 0.05 % of adenine) in C57BL/6J mice for 9 weeks. Progressive kidney damage led to reduced creatinine clearance, kidney fibrosis and renal inflammation after 3, 6, and 9 weeks. No difference in cardiac function, mitochondrial respiration nor left ventricular fibrosis was observed at any time point. Investigating mechanisms of renal damage, protective SirT3 was decreased in CKD, which contrasted an increase in protein kinase B (AKT) expression, mechanistic target of rapamycin (mTOR) downstream signaling, induction of oxidative and endo-plasmic reticulum (ER) stress. This occurred together with impaired renal mitochondrial function and accu-mulation of hexosylceramides (HexCer) as an established mediator of inflammation and mitochondrial dysfunction in the kidney.Conclusions: 2,8-DHA-induced CKD results in renal activation of the mTOR downstream signaling, endoplasmic reticulum stress, tubular injury, fibrosis, inflammation, oxidative stress and impaired kidney mitochondrial function in conjunction with renal hexosylceramide accumulation in C57BL/6J mice.
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