TRB3 is stimulated in diabetic kidneys, regulated by the ER stress marker CHOP, and is a suppressor of podocyte MCP-1.
The prevalence of diabetic nephropathy continues to rise, highlighting the importance of investigating and discovering novel treatment strategies. TRB3 is a kinase-like molecule that modifies cellular survival and metabolism and interferes with signal transduction pathways. Herein, we report that TRB3 expression is increased in the kidneys of type 1 and type 2 diabetic mice. TRB3 is expressed in conditionally immortalized podocytes; however, it is not stimulated by elevated glucose. The diabetic milieu is associated with increased oxidative stress and circulating free fatty acids (FFA). We show that reactive oxygen species (ROS) such as H(2)O(2) and superoxide anion (via the xanthine/xanthine oxidase reaction) as well as the FFA palmitate augment TRB3 expression in podocytes. C/EBP homologous protein (CHOP) is a transcription factor that is associated with the endoplasmic reticulum stress response. CHOP expression increases in diabetic mouse kidneys and in podocytes treated with ROS and FFA. In podocytes, transfection of CHOP increases TRB3 expression, and ROS augment recruitment of CHOP to the proximal TRB3 promoter. MCP-1/CCL2 is a chemokine that contributes to the inflammatory injury associated with diabetic nephropathy. In these studies, we demonstrate that TRB3 can inhibit basal and stimulated podocyte production of MCP-1. In summary, enhanced ROS and/or FFA associated with the diabetic milieu induce podocyte CHOP and TRB3 expression. Because TRB3 inhibits MCP-1, manipulation of TRB3 expression could provide a novel therapeutic approach in diabetic kidney disease.
Morse
Elizabeth
E
Schroth
Jana
J
You
Young-Hyun
YH
Pizzo
Donald P
DP
Okada
Shinichi
S
Ramachandrarao
Satish
S
Vallon
Volker
V
Sharma
Kumar
K
Cunard
Robyn
R
D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010168:Palmitates / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D050199:Podocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C491768:Ccl2 protein, mouse; D018797:Cell Cycle Proteins; D018932:Chemokine CCL2; D002843:Chromatin; D010168:Palmitates; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C474830:TRB3 protein, mouse; D051742:Transcription Factor CHOP; D004247:DNA