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

Autor: Ken Iseri, Masayuki Iyoda, Takanori Shibata, Nobuhiro Kanazawa, Kei Matsumoto, Taihei Suzuki, Shohei Tachibana, Yukihiro Wada
Rok vydání: 2020
Předmět:
protease-activated receptor
lcsh:Diseases of the circulatory (Cardiovascular) system
medicine.medical_specialty
Thrombomodulin
030232 urology & nephrology
lcsh:RC870-923
Rats
Inbred WKY
03 medical and health sciences
chemistry.chemical_compound
Idiopathic pulmonary fibrosis
0302 clinical medicine
Thrombin
Internal medicine
Thrombin receptor
lcsh:Dermatology
Renal fibrosis
Animals
Humans
Medicine
Renal Insufficiency
Chronic
Disseminated intravascular coagulation
Creatinine
Nephritis
business.industry
nephrotoxic serum nephritis
General Medicine
lcsh:RL1-803
lcsh:Diseases of the genitourinary system. Urology
medicine.disease
renal fibrosis
Rats
Endocrinology
chemistry
lcsh:RC666-701
Nephrology
Female
Cardiology and Cardiovascular Medicine
business
chronic kidney disease
Kidney disease
medicine.drug
Zdroj: Kidney & Blood Pressure Research, Pp 1-16 (2020)
ISSN: 1423-0143
1420-4096
DOI: 10.1159/000506286
Popis: 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.
Databáze: OpenAIRE
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