Dysfunction of the ER chaperone BiP accelerates the renal tubular injury.
Tubular-interstitial injury plays a key role in the progression of chronic kidney disease. Although endoplasmic reticulum (ER) stress plays significant roles in the development of chronic diseases such as neurodegenerative disease, cardiomyopathy and diabetes mellitus, its pathophysiological role in chronic renal tubular cell injury remains unknown. BiP is an essential chaperone molecule that helps with proper protein folding in the ER. Recently, we have produced a knock-in mouse that expresses a mutant-BiP in which the retrieval sequence to the ER is deleted in order to elucidate physiological processes that are sensitive to ER functions in adulthood. The heterozygous mutant-BiP mice showed significant tubular-interstitial lesions with aging. Furthermore, proteinuria induced by chronic protein overload accelerated the tubular-interstitial lesions in the mutant mice, accompanying caspase-12 activation and tubular cell apoptosis. These results suggest that the ER stress pathway is significantly involved in the pathophysiology of chronic renal tubular-interstitial injury in vivo.
Kimura
Keita
K
Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan.
Jin
Hisayo
H
Ogawa
Makoto
M
Aoe
Tomohiko
T
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D053454:Caspase 12 / Q000378:metabolism; D002417:Cattle; D004721:Endoplasmic Reticulum / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006579:Heterozygote; D006720:Homozygote; D007674:Kidney Diseases / Q000201:enzymology / Q000473:pathology*; D007684:Kidney Tubules / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011507:Proteinuria / Q000473:pathology; D012710:Serum Albumin, Bovine
D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D050505:Mutant Proteins; D012710:Serum Albumin, Bovine; D053454:Caspase 12