TRB3 is stimulated in diabetic kidneys, regulated by the ER stress marker CHOP,
and is a suppressor of podocyte MCP-1.
Authors Morse E, Schroth J, You YH, Pizzo DP, Okada S, Ramachandrarao S, Vallon V,
Sharma K, Cunard R
Submitted By Kumar Sharma on 5/2/2011
Status Published
Journal American journal of physiology. Renal physiology
Year 2010
Date Published 11/1/2010
Volume : Pages 299 : F965 - F972
PubMed Reference 20660016
Abstract 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.

Investigators with authorship
Kumar SharmaUniversity of California San Diego