Acute rejection after rat renal transplantation leads to downregulation of NA+ and water channels in the collecting duct.
Renal transplantation is associated with alterations of tubular functions and of the renin-angiotensin-aldosterone system. The underlying cellular and molecular mechanisms are unclear. We used an allogeneic rat renal transplantation model of acute rejection with and without immunosuppression by cyclosporine A (CsA) and a syngeneic model as control. Uninephrectomized Lewis or Lewis-Brown-Norway (LBN) rats received a kidney from LBN-rats. Renal transporters and receptors were analyzed by immunohistochemistry, semiquantitative RT-PCR and Western-blot analysis. Intracellular Na(+) was analyzed microfluorimetrically in isolated cortical collecting ducts. mRNA expression and function of the epithelial Na(+)-channel (ENaC) and mRNA and protein expression of the water-channel AQP2 were downregulated in transplanted kidneys undergoing rejection. Expression of the serum- and glucocorticoid-kinase (Sgk1) was decreased and that of the ubiquitin-protein ligase Nedd4-2 was increased. These changes were absent under CsA-therapy and in syngeneic model. Expression and function of the Na(+)-K(+)-ATPase, expression of the secretory K(+)-channel and of the mineralocorticoid receptor remained unchanged. Reduced ENaC function is likely due to decreased Sgk1- and increased Nedd4-2 mRNA expression leading to reduced ENaC expression in the membrane. These acute downregulations of ENaC and AQP2 may be triggered to reduce energy consumption in the distal nephron to protect the kidney immediately after transplantation.
Velic
Ana
A
Universitätsklinikum Münster, Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Münster, Germany.
Gabriëls
Gert
G
Hirsch
Jochen R
JR
Schröter
Rita
R
Edemir
Bayram
B
Paasche
Sandra
S
Schlatter
Eberhard
E
D000208:Acute Disease; D000818:Animals; D051399:Aquaporin 2; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D006084:Graft Rejection / Q000378:metabolism*; D017874:Immediate-Early Proteins; D016030:Kidney Transplantation; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D051399:Aquaporin 2; D020346:Aquaporins; D016572:Cyclosporine; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins; D015221:Potassium Channels; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D015222:Sodium Channels; D000254:Sodium-Potassium-Exchanging ATPase; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C496025:Aqp2 protein, rat; C000618479:NEDD4L protein, rat; C000618484:Nedd4 protein, rat