Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance.
Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.
Nakajo
Aya
A
Department of Pediatrics, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Khoshnoodi
Jamshid
J
Takenaka
Hitoshi
H
Hagiwara
Emi
E
Watanabe
Takashi
T
Kawakami
Hayato
H
Kurayama
Ryota
R
Sekine
Yuji
Y
Bessho
Fumio
F
Takahashi
Shori
S
Swiatecka-Urban
Agnieszka
A
Tryggvason
Karl
K
Yan
Kunimasa
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum; D000091342:Endoplasmic Reticulum Chaperone BiP; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D009404:Nephrotic Syndrome / Q000150:complications; D050199:Podocytes / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011507:Proteinuria / Q000139:chemically induced / Q000150:complications; D011692:Puromycin Aminonucleoside; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012263:Ribonucleosides / Q000494:pharmacology*; D013312:Stress, Physiological / Q000209:etiology / Q000503:physiopathology
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D012263:Ribonucleosides; C065171:cif nucleoside transporter; C113267:nephrin; C010052:mizoribine; D011692:Puromycin Aminonucleoside; D000255:Adenosine Triphosphate; D007168:IMP Dehydrogenase