Low-salt diet and cyclosporine nephrotoxicity: changes in kidney cell metabolism.
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-IKKγ and p65 proteins, thus activating NF-κB 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.
Department of Anesthesiology, University of Colorado, Aurora, Colorado, USA.|Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
Jelena
J
Klawitter
Department of Anesthesiology, University of Colorado, Aurora, Colorado, USA.
Jost
J
Klawitter
Department of Anesthesiology, University of Colorado, Aurora, Colorado, USA.|Department of General-, Visceral- and Transplantation Surgery, Charité, Campus Virchow, Berlin, Germany.
Volker
V
Schmitz
Department of Anesthesiology, University of Colorado, Aurora, Colorado, USA.|Department of General-, Visceral- and Transplantation Surgery, Charité, Campus Virchow, Berlin, Germany.
Nina
N
Brunner
Department of Anesthesiology, University of Colorado, Aurora, Colorado, USA.
Amanda
A
Crunk
Department of Anesthesiology, University of Colorado, Aurora, Colorado, USA.
Kyler
K
Corby
Department of Anesthesiology, University of Colorado, Aurora, Colorado, USA.
Jamie
J
Bendrick-Peart
Institute for Organic Chemistry, Universität Bremen, Bremen, Germany.
Dieter
D
Leibfritz
Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
Charles L
CL
Edelstein
Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.
Joshua M
JM
Thurman
Department of Anesthesiology, University of Colorado, Aurora, Colorado, USA.
Uwe
U
Christians
D000818:Animals; D015153:Blotting, Western; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000633:toxicity*; D015180:Electrophoresis, Gel, Two-Dimensional; D005943:Gluconeogenesis; D006019:Glycolysis; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D017136:Ion Transport; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018384:Oxidative Stress; D010710:Phosphates / Q000378:metabolism; D040901:Proteomics; D051381:Rats; D017208:Rats, Wistar; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage*; D014018:Tissue Distribution
D007166:Immunosuppressive Agents; D010710:Phosphates; D017673:Sodium Chloride, Dietary; D016572:Cyclosporine