Differential expression of endoplasmic reticulum stress-response   proteins in different renal tubule subtypes of OVE26 diabetic mice.
Regulation of the endoplasmic reticulum (ER) stress-response pathway during the course of diabetes specifically in renal tubules is unclear. Since tubule cell dysfunction is critical to progression of diabetic nephropathy, this study analyzed markers of ER stress response and ER chaperones at different stages of diabetes and in different renal tubule subtypes of OVE26 type-1 diabetic mice. ER stress-responseinduced chaperones GRP78, GRP94, and protein disulfide isomerase (PDI) were increased in isolated cortical tubules of older diabetic mice, while PDI was decreased in tubules of young diabetic mice. Immunofluorescence staining of kidneys from older mice showed GRP78 and PDI upregulation in all cortical tubule segments, with substantial induction of PDI in distal tubules. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) phosphorylation was increased in cortical tubules of young diabetic mice, with no differences between older diabetic and control mice. Expression of ER stress-induced PERK inhibitor p58IPK was decreased and then increased in all tubule subtypes of young and older mice, respectively. Knockdown of PERK by small interfering RNA (siRNA) increased fibronectin secretion in cultured proximal tubule cells. Tubules of older diabetic mice had significantly more apoptotic cells, and ER stress-induced proapoptotic transcription factor C/EBP homologous protein (CHOP) was increased in proximal and distal tubules of diabetic mice and diabetic humans. CHOP induction in OVE26 mice was not altered by severity of proteinuria. Overexpression of CHOP in cultured proximal tubule cells increased expression of fibronectin. These findings demonstrate differential ER stress-response signaling in tubule subtypes of diabetic mice and implicate a role for PERK and CHOP in tubule cell matrix protein production.
Kidney Disease Program, Department of Medicine, University of Louisville, 570 S. Preston St., Room 102, Louisville, KY, 40202, USA. michelle.barati@louisville.edu.
Michelle T
MT
Barati
Kidney Disease Program, Department of Medicine, University of Louisville, 570 S. Preston St., Room 102, Louisville, KY, 40202, USA.|Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY, USA.
David W
DW
Powell
Kidney Disease Program, Department of Medicine, University of Louisville, 570 S. Preston St., Room 102, Louisville, KY, 40202, USA.
Bobak D
BD
Kechavarzi
Kidney Disease Program, Department of Medicine, University of Louisville, 570 S. Preston St., Room 102, Louisville, KY, 40202, USA.
Susan M
SM
Isaacs
Department of Pediatrics, University of Louisville, Louisville, KY, USA.
Shirong
S
Zheng
Department of Pediatrics, University of Louisville, Louisville, KY, USA.
Paul N
PN
Epstein
Department of Pediatrics, University of Louisville, Louisville, KY, USA.
Lu
L
Cai
Department of Pediatric Pathology, University of Louisville, Louisville, KY, USA.
Susan
S
Coventry
Kidney Disease Program, Department of Medicine, University of Louisville, 570 S. Preston St., Room 102, Louisville, KY, 40202, USA.|Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY, USA.
Madhavi J
MJ
Rane
Kidney Disease Program, Department of Medicine, University of Louisville, 570 S. Preston St., Room 102, Louisville, KY, 40202, USA.|Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY, USA.
Jon B
JB
Klein
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D003920:Diabetes Mellitus / Q000473:pathology*; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D019704:Protein Disulfide-Isomerases / Q000096:biosynthesis; D011507:Proteinuria / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D000091342:Endoplasmic Reticulum Chaperone BiP; D005353:Fibronectins; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D019704:Protein Disulfide-Isomerases; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497250:Ddit3 protein, mouse; C500846:Dnajc3 protein, mouse; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C053387:endoplasmin