Two routes to cell death in the diseased kidney

September 12, 2001

Stimulation by the ubiquitous cytokine TGF-b activates the transcription of numerous target genes and leads to an impressive range of biological effects. Central to these responses are intracellular mediators of the SMAD family, which are activated and transported to the nucleus following TGF-b treatment. Schiffer et al. show here that there are surprises left in this widely studied and highly conserved pathway. Overexpression of TGF-b1 under control of the Albumin promoter causes apoptosis in renal epithelial cells and yields a model of glomerulosclerosis, a progressive disease involving glomerular fibrosis and degeneration. One protein of the SMAD family, SMAD7, is well known as a negative regulator of TGF-b signaling, and indeed, TGF-b signaling often activates synthesis of SMAD7, establishing a negative feedback system that can limit the pathway?s physiological effects. Schiffer and colleagues now find, however, that SMAD7 can also carry its own signals and can work in parallel with TGF-b. In glomerulosclerosis, the cell death induced by the overexpression of the cytokine is accompanied by a dramatic increase in SMAD7, which acts independently in this system to induce apoptosis. Even without TGF-b overexpression, cultured renal podocytes that express SMAD7 are prone to apoptosis. This response activates different apoptotic effectors and is mediated by a signaling pathway distinct from the one induced by TGF-b. Whether SMAD7 must interact with the stimulatory SMAD proteins to exert this novel effect is not yet known.

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