BIGH3 dependent renal cell apoptosis and the role of macrophage-derived TGFbeta1




Moritz, Robert Joseph

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Diabetes mellitus associated renal damage is characterized by the recruitment of macrophages to the renal cortex and an accumulation of extracellular cellular matrix (ECM) molecules. Transforming Growth Factor Beta- Induced Gene Human Clone 3 (BIGH3) is a secreted, pro-apoptotic ECM molecule distinguished by an increased rate of synthesis in many cells stimulated with Transforming growth factor beta (TGFbeta). Macrophages have been shown to be a source of secreted TGFbeta1, and BIGH3 levels are found to be elevated in the diabetic kidney. Our previous studies have detected an increased synthesis of BIGH3 in response to TGFbeta1 in the kidney, eye and vasculature of mice and human cells in culture. These studies have also detected an increase in levels of detected apoptosis of kidney and eye cells cultured in an accumulation of BIGH3. This study further pursues these findings by demonstrating a dose-dependent apoptotic response in human renal proximal tubule epithelial cells (RPTEC). Additionally, we attenuated an apoptotic response in RPTEC cultured in medium enriched with macrophage-derived factors through the use of antibodies and agents which neutralize elements of the TGFbeta1 signaling pathway. The dynamics of these responses are explored by comparing rates of BIGH3 mRNA expression and quantified levels of apoptosis in RPTEC stimulated with factors derived from macrophages cultured under normal and diabetic conditions. These data explore a mechanistic relationship between TGFbeta1 derived from macrophages in a diabetic environment, the expression and accumulation of BIGH3, and induced apoptosis in renal cells.


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apoptosis, BIGH3, Renal, TGFB1



Integrative Biology