Macrophage induction of BIGH3-mediated apoptosis: A novel mechanism promoting diabetic complications in the renal system




Hardikar, Swanand

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Transforming Growth Factor Beta -- Induced G ene Human Clone 3 (BIGH-3) is an extracellular proapoptotic protein molecule. BIGH3 is upregulated by TGFbeta-1 and expressed in adult tissues during embryonic development. Earlier studies have shown that type 2 diabetic human kidney cortex showed a 10-fold increase in BIGH3 expression when compared to a similarly aged non-diabetic human kidney cortex. Our previous studies detected elevated levels of BIGH3 in tissues from diabetic mice, including eye, kidney, and the vasculature. Here we discuss BIGH3 as an important molecule in TGFbeta-evoked apoptosis. We hypothesize that macrophages are intimately involved in BIGH3 expression that induces apoptosis of renal proximal tubule epithelial cells (RPTEC). In the this study we show that BIGH3 expression is upregulated in RPTE cells cultured in medium supplemented with macrophage conditioned medium (MCM), thus implicating a role of macrophage-derived signaling molecule that are able to activate the BIGH3 gene in RPTE cells. We also showed that blocking antibodies directed against TGFbeta-1, and TGFbeta receptor blockers, prevented diabetic-MCM induced BIGH3 expression which in turn reduced apoptosis, strongly implicating that TGFbeta cytokines as BIGH3 gene inducers in the MCM. Moreover, we showed that recombinant BIGH3 evoked a significant increase in RPTE cell apoptosis in vitro, and plan to show that caspase-3 was activated in the pathway. In summary, this study demonstrates that in vitro macrophage-derived TGFbeta is responsible for the increased secretion of BIGH3 that contributes to renal cell apoptosis. Renal cell apoptosis contributes to diabetic renal disease progression. Therefore, macrophages, their cytokines, and BIGH3 itself may be attractive targets for intervention in diabetic complications and the kidney.


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Apoptosis, Diabetes, Kidney, Renal, RPTE cells



Integrative Biology