Low-Salt Diet and Cyclosporine Nephrotoxicity: Changes in Kidney Cell Metabolism
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- 作者：Jelena Klawitter ; Jost Klawitter ; Volker Schmitz ; Nina Brunner ; Amanda Crunk ; Kyler Corby ; Jamie Bendrick-Peart ; Dieter Leibfritz ; Charles L. Edelstein ; Joshua M. Thurman ; Uwe Christians
- 刊名：Journal of Proteome Research
- 出版年：2012
- 出版时间：November 2, 2012
- 年：2012
- 卷：11
- 期：11
- 页码：5135-5144
- 全文大小：414K
- 年卷期：v.11,no.11(November 2, 2012)
- ISSN：1535-3907
文摘
Cyclosporine (CsA) is a highly effective immunosuppressant used in patients after transplantation; however, its use is limited by nephrotoxicity. Salt depletion is known to enhance CsA-induced nephrotoxicity in the rat, but the underlying molecular mechanisms are not completely understood. The goal of our study was to identify the molecular effects of salt depletion alone and in combination with CsA on the kidney using a proteo-metabolomic strategy. Rats (n = 6) were assigned to four study groups: (1) normal controls, (2) low-salt fed controls, (3) 10 mg/kg/d CsA for 28 days on a normal diet, (4) 10 mg/kg/d CsA for 28 days on low-salt diet. Low-salt diet redirected kidney energy metabolism toward mitochondria as indicated by a higher energy charge than in normal-fed controls. Low-salt diet alone reduced phospho-AKT and phospho-STAT3 levels and changed the expression of ion transporters PDZK1 and CLIC1. CsA induced macro- and microvesicular tubular epithelial vacuolization and reduced energy charge, changes that were more significant in low-salt fed animals, probably because of their more pronounced dependence on mitochondria. Here, CsA increased phospho-JAK2 and phospho-STAT3 levels and reduced the phospho-IKK纬 and p65 proteins, thus activating NF-魏B signaling. Decreased expression of lactate transport regulator CD147 and phospho-AKT was also observed after CsA exposure in low-salt rats, indicating a decrease in glycolysis. In summary, our study suggests a key role for PDZK1, CD147, JAK/STAT, and AKT signaling in CsA-induced nephrotoxicity and proposes mechanistic explanations on why rats fed a low-salt diet have higher sensitivity to CsA.