Tolvaptan, a selective oral vasopressin V2 receptor antagonist, ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats.
BACKGROUND
Proteinuria caused by glomerular disease is characterized by podocyte injury. Vasopressin V2 receptor antagonists are effective in reducing albuminuria, although their actions on glomerular podocytes have not been explored. The objective of this study was to evaluate the effects of tolvaptan, a selective oral V2 receptor antagonist, on podocytes in a puromycin aminonucleoside (PAN)-induced nephrosis rat model.


METHODS
Rats were allocated to a control, PAN nephrosis, or tolvaptan-treated PAN nephrosis group (n = 9 per group). Urinary protein excretion and serum levels of total protein, albumin, creatinine, and total cholesterol were measured on day 10. The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy.


RESULTS
PAN induced massive proteinuria and serum creatinine elevation on day 10, both of which were significantly ameliorated by tolvaptan. Immunofluorescence studies of the podocyte-associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats. In tolvaptan-treated rats, nephrin and podocin expressions retained their normal linear pattern. Electron microscopy showed foot process effacement was ameliorated in tolvaptan-treated rats.


CONCLUSIONS
Tolvaptan is protective against podocyte damage and proteinuria in PAN nephrosis. This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis. Tolvaptan is a promising pharmacological tool in the treatment of renal edema.
Okada
Tadashi
T
Division of Nephrology and Blood Purification Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-0012, Japan. tad-okada@umin.ac.jp.
Sakaguchi
Toshifumi
T
Division of Nephrology and Blood Purification Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-0012, Japan.
Hatamura
Ikuji
I
First Department of Pathology, Wakayama Medical University, Wakayama, Japan.
Saji
Fumie
F
Division of Nephrology and Blood Purification Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-0012, Japan.
Negi
Shigeo
S
Division of Nephrology and Blood Purification Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-0012, Japan.
Otani
Haruhisa
H
Division of Nephrology and Blood Purification Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-0012, Japan.|Ryoshukai Wakayama Kidney Disease Clinic, Wakayama, Japan.
Muragaki
Yasuteru
Y
First Department of Pathology, Wakayama Medical University, Wakayama, Japan.
Kawachi
Hiroshi
H
Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Shigematsu
Takashi
T
Division of Nephrology and Blood Purification Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-0012, Japan.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000627:therapeutic use*; D003893:Desmin / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009401:Nephrosis / Q000139:chemically induced / Q000188:drug therapy; D009929:Organ Size; D050199:Podocytes / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D011692:Puromycin Aminonucleoside / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077602:Tolvaptan; D025721:WT1 Proteins / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D003893:Desmin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D025721:WT1 Proteins; C113267:nephrin; D000077602:Tolvaptan; D011692:Puromycin Aminonucleoside