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. 2024 Jan;1870(1):166825.
doi: 10.1016/j.bbadis.2023.166825. Epub 2023 Aug 1.

2,8-Dihydroxyadenine-induced nephropathy causes hexosylceramide accumulation with increased mTOR signaling, reduced levels of protective SirT3 expression and impaired renal mitochondrial function

Julia Moellmann  1 , Katja Krueger  1 , Dickson W L Wong  2 , Barbara M Klinkhammer  2 , Eva M Buhl  3 , Jonas Dehairs  4 , Johan V Swinnen  4 , Heidi Noels  5 , Joachim Jankowski  5 , Corinna Lebherz  1 , Peter Boor  6 , Nikolaus Marx  1 , Michael Lehrke  7
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Free article

2,8-Dihydroxyadenine-induced nephropathy causes hexosylceramide accumulation with increased mTOR signaling, reduced levels of protective SirT3 expression and impaired renal mitochondrial function

Julia Moellmann et al. Biochim Biophys Acta Mol Basis Dis. 2024 Jan.
Free article

Abstract

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 endoplasmic reticulum (ER) stress. This occurred together with impaired renal mitochondrial function and accumulation 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.

Keywords: 2,8-Dihydroxyadenine nephropathy; Chronic kidney disease; Endoplasmic reticulum stress; Hexosylceramides; Mitochondrial function; mTOR.

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Conflict of interest statement

Declaration of competing interest NM has given lectures for Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, NovoNordisk; has received unrestricted research grants from Boehringer Ingelheim, and has served as an advisor for Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, NovoNordisk. In addition, served in trial leadership for Boehringer Ingelheim and NovoNordisk. ML received grants and personal fees from Boehringer Ingelheim, MSD, Novo Nordisk and personal fees from Amgen, Sanofi, Astra Zeneca, Bayer, Lilly, Daiichi Sankyo, Novarits. NM, HN and JJ are founding shareholders of AMICARE Development GmbH. JM, KK, BMK, DWLW, EMB, JD, JVS, CL and PB have nothing to disclose.

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