Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.

Apoptosis signal-regulating kinase (ASK) 1 was recently identified as a mitogen-activated protein (MAP) kinase kinase kinase which activates the c-Jun N-terminal kinase (JNK) and p38 MAP kinase pathways and is required for tumor necrosis factor (TNF)-alpha-induced apoptosis; however, the mechanism regulating ASK1 activity is unknown. Through genetic screening for ASK1-binding proteins, thioredoxin (Trx), a reduction/oxidation (redox)-regulatory protein thought to have anti-apoptotic effects, was identified as an interacting partner of ASK1. Trx associated with the N-terminal portion of ASK1 in vitro and in vivo. Expression of Trx inhibited ASK1 kinase activity and the subsequent ASK1-dependent apoptosis. Treatment of cells with N-acetyl-L-cysteine also inhibited serum withdrawal-, TNF-alpha- and hydrogen peroxide-induced activation of ASK1 as well as apoptosis. The interaction between Trx and ASK1 was found to be highly dependent on the redox status of Trx. Moreover, inhibition of Trx resulted in activation of endogenous ASK1 activity, suggesting that Trx is a physiological inhibitor of ASK1. The evidence that Trx is a negative regulator of ASK1 suggests possible mechanisms for redox regulation of the apoptosis signal transduction pathway as well as the effects of antioxidants against cytokine- and stress-induced apoptosis.

Mature tubular epithelial cells in adult kidney can undergo epithelial-to-mesenchymal transition (EMT), a phenotypic conversion that is fundamentally linked to the pathogenesis of renal interstitial fibrosis. Emerging evidence indicates that a large proportion of interstitial fibroblasts are actually originated from tubular epithelial cells via EMT in diseased kidney. Moreover, selective blockade of EMT in a mouse genetic model dramatically reduces fibrotic lesions after obstructive injury, underscoring a definite importance of EMT in renal fibrogenesis. Tubular EMT is proposed as an orchestrated, highly regulated process that consists of four key steps: (1) loss of epithelial cell adhesion; (2) de novo alpha-smooth muscle actin expression and actin reorganization; (3) disruption of tubular basement membrane; and (4) enhanced cell migration and invasion. Of the many factors that regulate EMT in different ways, transforming growth factor-beta1 is the most potent inducer that is capable of initiating and completing the entire EMT course, whereas hepatocyte growth factor and bone morphogenetic protein-7 act as EMT inhibitors both in vitro and in vivo. Multiple intracellular signaling pathways have been implicated in mediating EMT, in which Smad/integrin-linked kinase may play a central role. This article attempts to provide a comprehensive review of recent advances on understanding the pathologic significance, molecular mechanism, and therapeutic intervention of EMT in the setting of chronic renal fibrosis.