Therapeutic Potential of Thrombomodulin in Renal Fibrosis of Nephrotoxic Serum Nephritis in Wistar-Kyoto Rats

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Abstract

Background: Recombinant human soluble thrombomodulin (rhTM) was approved in 2008 and has been used for treatment of disseminated intravascular coagulation in Japan. The antifibrotic effects of rhTM in acute exacerbation of idiopathic pulmonary fibrosis are well established, but the therapeutic potential of rhTM in renal fibrosis remains poorly understood. Methods: Nephrotoxic serum nephritis (NTS-N) was induced in 22 female Wistar-Kyoto (WKY) rats on day 0. Rats were administered either rhTM or vehicle intraperitoneally, every day from day 4 to day 55. Rats were sacrificed on day 56 when renal fibrosis was established and renal morphological investigations were performed. In vitro, rat renal fibroblasts (NRK-49F) were pretreated with rhTM or saline, and expression levels of profibrogenic gene induced by thrombin were analyzed by real-time reverse transcription polymerase chain reaction. Results: Compared to WKY-GN-vehicle rats, the body weights of WKY-GN-rhTM rats were significantly greater on day 55. By day 56, rhTM had significantly reduced serum creatinine levels in NTS-N. On the other hand, urinary protein excretion was comparable between the two treatment groups throughout the study. The percentage of Masson trichrome-positive areas in WKY-GN-rhTM rats was significantly lower compared to that in WKY-GN-vehicle rats. Glomerular fibrin deposition was significantly reduced in WKY-GN-rhTM rats. In addition, rhTM significantly reduced the renal cortical mRNA expression levels of TNF-α, Toll-like receptor 4, MYD88, TGF-β, αSMA, collagen I, collagen III, fibronectin, and protease-activated receptor 1 (PAR1), a thrombin receptor. In vitro, thrombin stimulation of NRK-49F cells significantly enhanced the mRNA expression levels of αSMA and PAR1, and these upregulations were significantly reduced by pretreatment with rhTM. Conclusions: Administration of rhTM after establishment of crescentic glomerulonephritis (GN) attenuated the subsequent development of renal fibrosis in NTS-N, possibly in part by inhibiting thrombin-mediated fibrogenesis. Our results suggest that rhTM may offer a therapeutic option for limiting the progression of chronic kidney disease in crescentic GN.

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Most cited references 51

Record: found
Abstract: found
Article: not found

Origin and function of myofibroblasts in kidney fibrosis.

Theodore D V Cooke, Timothy Cooke, H Sugimoto … (2013)

Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.

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Record: found
Abstract: found
Article: not found

Renal fibrosis: new insights into the pathogenesis and therapeutics.

Youhua Liu (2005)

Renal fibrosis is the inevitable consequence of an excessive accumulation of extracellular matrix that occurs in virtually every type of chronic kidney disease. The pathogenesis of renal fibrosis is a progressive process that ultimately leads to end-stage renal failure, a devastating disorder that requires dialysis or kidney transplantation. In a simplistic view, renal fibrosis represents a failed wound-healing process of the kidney tissue after chronic, sustained injury. Several cellular pathways, including mesangial and fibroblast activation as well as tubular epithelial-mesenchymal transition, have been identified as the major avenues for the generation of the matrix-producing cells in diseased conditions. Among the many fibrogenic factors that regulate renal fibrotic process, transforming growth factor-beta (TGF-beta) is one that plays a central role. Although defective matrix degradation may contribute to tissue scarring, the exact action and mechanisms of the matrix-degrading enzymes in the injured kidney have become increasingly complicated. Recent discoveries on endogenous antifibrotic factors have evolved novel strategies aimed at antagonizing the fibrogenic action of TGF-beta/Smad signaling. Many therapeutic interventions appear effective in animal models; however, translation of these promising results into humans in the clinical setting remains a daunting task. This mini-review attempts to highlight the recent progress in our understanding of the cellular and molecular pathways leading to renal fibrosis, and discusses the challenges and opportunities in developing therapeutic strategies.

0 comments Cited 204 times – based on 0 reviews      Review now

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Record: found
Abstract: found
Article: not found

Tubulointerstitial changes as a major determinant in the progression of renal damage.

Karl A. Nath (1992)

Tubulointerstitial injury is an invariant finding in the chronically diseased kidney, irrespective of the type of disease or the compartment in which the disease originates. Such histologic changes are functionally significant in that scores for such damage, rather than glomerular injury, correlate with decline of renal function. This review summarizes (1) clinical evidence attesting to tubulointerstitial changes as an index of functional impairment, (2) mechanisms by which tubulointerstitial injury impairs renal function, and (3) interactions of pathologic processes in the vascular, glomerular, tubular, and interstitial compartments that culminate in tubulointerstitial injury. This report concludes with a review of interstitial fibrosis, a pathologic process regarded as an irreversible outcome from tubulointerstitial injury.

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Author and article information

Journal

Journal ID (publisher-id): KBR

Journal ID (nlm-ta): Kidney Blood Press Res

Journal ID (doi): 10.1159/issn.1420-4096

Title: Kidney and Blood Pressure Research

Publisher: S. Karger AG

ISSN (Print): 1420-4096

ISSN (Electronic): 1423-0143

Publication date Subscription-year: 2020

Publication date (Print): May 2020

Publication date (Electronic): 06 March 2020

Volume: 45

Issue: 3

Pages: 391-406

Affiliations

Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan

Author notes

*Masayuki Iyoda, Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666 (Japan), iyoda@med.showa-u.ac.jp

Article

Publisher ID: 506286 Other ID: Kidney Blood Press Res 2020;45:391–406

DOI: 10.1159/000506286

PubMed ID: 32146474

License:

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