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TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis

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Abstract

Chronic kidney disease constitutes an increasing medical burden affecting 26 million people in the United States alone. Diabetes, hypertension, ischemia, acute injury, and urological obstruction contribute to renal fibrosis, a common pathological hallmark of chronic kidney disease. Regardless of etiology, elevated TGF-β1 levels are causatively linked to the activation of profibrotic signaling pathways initiated by angiotensin, glucose, and oxidative stress. Unilateral ureteral obstruction (UUO) is a useful and accessible model to identify mechanisms underlying the progression of renal fibrosis. Plasminogen activator inhibitor-1 (PAI-1), a major effector and downstream target of TGF-β1 in the progression of several clinically important fibrotic disorders, is highly up-regulated in UUO and causatively linked to disease severity. SMAD and non-SMAD pathways (pp60c-src, epidermal growth factor receptor [EGFR], mitogen-activated protein kinase, p53) are required for PAI-1 induction by TGF-β1. SMAD2/3, pp60c-src, EGFR, and p53 activation are each increased in the obstructed kidney. This review summarizes the molecular basis and translational significance of TGF-β1-stimulated PAI-1 expression in the progression of kidney disease induced by ureteral obstruction. Mechanisms discussed here appear to be operative in other renal fibrotic disorders and are relevant to the global issue of tissue fibrosis, regardless of organ site.

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  1. Center for Cell Biology and Cancer Research (MC-165), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA

    Rohan Samarakoon, Jessica M. Overstreet, Stephen P. Higgins & Paul J. Higgins

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  1. Rohan Samarakoon
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  2. Jessica M. Overstreet
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  3. Stephen P. Higgins
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  4. Paul J. Higgins
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Correspondence to Paul J. Higgins.

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This work was supported by NIH grant R01 GM057242.

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Samarakoon, R., Overstreet, J.M., Higgins, S.P. et al. TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis. Cell Tissue Res 347, 117–128 (2012). https://doi.org/10.1007/s00441-011-1181-y

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