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

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.

Retracted: MircoRNA‐1275 promotes proliferation, invasion and migration of glioma cells via SERPINE1

“…On the other hand, wild‐type p53 could repair the cells even with genetic abnormalities31 and might cause drug resistance to temozolomide 32. SERPINE1 was generally considered as the downstream gene of p53 and could be induced by the activation of p53 33, 34. However, our study found that the up‐regulation of SERPINE1 repressed p53 signalling pathway, whereas miR‐1275 had an inverse effect, which has not been reported in previous studies.…”

Androgen Deprivation Induces Bladder Histological Abnormalities and Dysfunction via TGF-.BETA. in Orchiectomized Mature Rats

“…TGF-β 1 is a common profibrotic factor that mediates the pathologic process of fibrosis in multiple organs (Matsuoka and Tsukamoto 1990;Wen et al 2010;Lang et al 2011;Samarakoon et al 2012). Matsuoka and Tsukamoto (1990) found that TGF-β 1 plays critical role in pathogenetic role in alcoholic liver fibrogenesis by stimulation of hepatic lipocyte collagen production.…”

“…However the intermediate molecule and signaling pathway are unknown. Realizing that TGF-β 1 is a common profibrotic factor which mediates the pathologic process of fibrosis in multiple organs (Matsuoka and Tsukamoto 1990;Wen et al 2010;Lang et al 2011;Samarakoon et al 2012), we hypothesize that TGF-β 1 is responsible for androgen deprivation-induced fibrosis in bladder tissues. To test this hypothesis, firstly we measured the TGF-β 1 mRNA levels Androgen deprivation induced TGF-β production contributes to induction of pro-collagen I mRNA expression level.…”

Glucosamine and caveat emptor

“…One confounding variable is the correctness of the UUO model in terms of the primary role of myofibroblasts and TGF-β1. A recent review supports the interpretation of Park et al [6] and other observers [8]. However, what if this view is oversimplified or not correct?…”