Dobberfuhl et al., Cell Dev Biol 2012, 1:3 DOI: 10.4172/2168-9296.1000e107 Volume 1 • Issue 3 • 1000e107 Open Access Editorial Ureteral Obstruction-Induced Renal Fibrosis: An In Vivo Platform for Mechanistic Discovery and Therapeutic Intervention Amy D. Dobberfuhl 1 , Rohan Samarakoon 2 , Craig E. Higgins 2 , Badar M. Mian 2 , Jessica M. Overstreet 2 , Stephen P. Higgins 2 , Barry A. Kogan 2 and Paul J. Higgins 2 * 1 The Urological Institute of Northeastern New York, Albany NY 12208, USA 2 Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany NY 12208, USA *Corresponding author: Dr. Paul J. Higgins, Center for Cell Biology & Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA, Tel: 518-262-5168; E-mail: higginp@mail.amc.edu Received June 30, 2012; Accepted July 02, 2012; Published July 03, 2012 Citation: Dobberfuhl AD, Samarakoon R, Higgins CE, Mian BM, Overstreet JM, et al. (2012) Ureteral Obstruction-Induced Renal Fibrosis: An In Vivo Platform for Mechanistic Discovery and Therapeutic Intervention. Cell Dev Biol 1:e107. doi:10.4172/2168-9296.1000e107 Copyright: © 2012 Dobberfuhl AD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Molecular Events Associated with Renal Fibrosis: TGF-β/SMAD Signaling as Transducer of the Fibrotic Phenotype Interstitial fbrosis, resulting in renal tissue destruction and progressive impairment of organ function, is a hallmark of end-stage kidney disease [1]. Te primary sources of matrix synthesis during renal fbrogenesis are activated fbroblasts or myofbroblasts. While their origin remains uncertain, this cell type-predictor of disease progression likely derives largely from resident fbroblasts and epithelial-to-mesenchymal transdiferentiated (EMT) tubular epithelial cells [2]. Te transforming growth factor-β (TGF-β)/SMAD system is a potent, perhaps the most well-characterized, inducer of myofbroblast diferentiation and EMT. TGF-β drives EMT in renal epithelial cells and promotes fbrosis in animal models by engaging efector pathways and their downstream target genes that impact both the infammatory and scarring stages of the injury response [3]. SMAD-mediated signaling initiated by TGF-β is pivotal for induction of EMT, fbroblast activation and renal fbrosis [2,3]. SMAD3, in particular, appears critical in several in vivo models of renal fbrosis. Tis was, indeed, confrmed by the fnding that SMAD3-defcient mice are signifcantly protected from disease progression. TGF-β also activates non-SMAD-dependent pathways [4] that impact the expression of pro-fbrotic genes. Te continued characterization of such highly-interactive transduction events initiated by TGF-β/TGF-β receptor interactions will likely lead to identifcation of novel opportunities for anti-fbrotic therapy. Animal Models for Investigating Obstructive Nephropathies and the Signaling Mechanisms Associated with Renal Fibrosis Ureteral Unilateral Obstruction (UUO) is an established, relatively short-term, animal model of injury-stimulated renal fbrosis that lends itself to the dissection of critical mechanistic events and evaluation of potential therapeutic targets [5]. Aside from its relative surgical ease, UUO in rodents is pathophysiologically-relevant and recapitulates the biology of human nephropathy associated with congenital urinary tract anomalies (common in pediatric patients), obstructive urolithiasis and age-related lower urinary tract obstruction. Te basic pathology of UUO in murine systems is highly reproducible. Within hours afer ureteral occlusion, the afected kidney is subject to sudden changes in mechanical forces, increased oxidative stress upon generation of free radicals and tissue ischemia resulting in a complex phenotypic response including cellular apoptosis, infammation (due to infltrating macrophages and expression of infammatory cytokines), alterations in gene expression, extracellular matrix (ECM) remodeling and EMT. “Activated” fbroblasts derived from resident interstitial fbroblasts, recruited from extra-renal sources (i.e., the circulation) or arising de novo from EMT of the injured epithelium diferentiate into matrix- secreting myofbroblasts and initiate the process of ECM deposition. With persistence of obstruction, overt fbrosis and massive epithelial apoptosis develops with eventual tubular atrophy and loss of renal function. Tubulointerstitial fbrosis in this model appears dependent on upregulation of TGF-β1 expression in the interstitial compartment. Indeed, introduction of 15-mer TGF-β1 antisense phosphorothioate oligodeoxynucleotides by retrograde ureteral injection or administration of TGF-β1 siRNA suppresses tubulointerstitial fbrosis in UUO with reduced expression of the TGF-β1 response genes. Consistent with the activation of TGF-β1 signaling in UUO, there is a dramatic increase of SMAD2/3 phosphorylation and elevated expression of plasminogen activator inhibitor-1 (SERPINE1, PAI-1) in the obstructed kidney compared to the contralateral controls [2]. PAI-1 is particularly important in the overall context of tissue fbrosis regardless of site and a prominent downstream target of the TGF-β1/ SMAD3 [4,5]. A major inhibitor of plasmin generation, PAI-1 inhibits ECM degradation, thereby, contributing to interstitial fbrosis. PAI-1 null mice are, in fact, signifcantly protected from renal fbrosis and excessive ECM accumulation. Increased PAI-1 expression has been implicated in various animal models of renal diseases and is highly induced by pro-fbrogenic and pro-infammatory mediators including angiotensin, CTGF, interleukins and TNF-α . PAI-1 null mice subjected UUO, moreover, exhibit a signifcantly reduced infammatory response compared to wild-type controls suggesting that this SERPIN may promote infltration of macrophages and T-cells. PAI-1 also modulates TGF-β1 signaling as PAI-1-null animals (compared to wild-type controls subjected to obstructive nephropathy) have lower TGF-β1 levels. Recombinant PAI-1, in fact, activates the TGF-β1 promoter suggesting that PAI-1 may initiate, and perhaps maintain, a potential pro-fbrogenic “loop” in the context of renal disease. Hence, targeted down-modulation of PAI-1 may provide signifcant, multiple-level, therapeutic value in inhibiting fbrosis onset and progression as well as in the more difcult clinical challenge of disease reversal. It is anticipated that cell & developmental biology will be an efective vehicle to communicate these translationally-important fndings to the biomedical research community. Acknowledgements This work was supported by NIH grant GM057242. The authors regret that space did not allow for citation of many of our colleagues important contributions. Detailed descriptions of work discussed in this editorial, complete with appropriate literature citations, can be found in the following recent publications: C e l l & D e v e l o p m e n t a l B i o l o g y ISSN: 2168-9296 Cell & Developmental Biology