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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Renoprotective Effects of a Novel Receptor-Interacting Protein Kinase 2 Inhibitor, AS3334034, in Uninephrectomized Adriamycin-Induced Chronic Kidney Disease Rats

Yusuke Wada, Mitsuhiro Kondo, Kumi Sakairi, Akira Nagashima, Kenichi Tokita, Hiroaki Tominaga, Hiroshi Tomiyama and Tomohisa Ishikawa
Journal of Pharmacology and Experimental Therapeutics September 2020, 374 (3) 428-437; DOI: https://doi.org/10.1124/jpet.120.265678
Yusuke Wada
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan (Y.W., M.K., K.S., A.N., K.T., H.T.); Research and Development Department, Kotobuki Pharmaceutical Co., Ltd., Nagano, Japan (H.T.); and Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (Y.W., T.I.)
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Mitsuhiro Kondo
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan (Y.W., M.K., K.S., A.N., K.T., H.T.); Research and Development Department, Kotobuki Pharmaceutical Co., Ltd., Nagano, Japan (H.T.); and Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (Y.W., T.I.)
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Kumi Sakairi
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan (Y.W., M.K., K.S., A.N., K.T., H.T.); Research and Development Department, Kotobuki Pharmaceutical Co., Ltd., Nagano, Japan (H.T.); and Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (Y.W., T.I.)
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Akira Nagashima
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan (Y.W., M.K., K.S., A.N., K.T., H.T.); Research and Development Department, Kotobuki Pharmaceutical Co., Ltd., Nagano, Japan (H.T.); and Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (Y.W., T.I.)
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Kenichi Tokita
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan (Y.W., M.K., K.S., A.N., K.T., H.T.); Research and Development Department, Kotobuki Pharmaceutical Co., Ltd., Nagano, Japan (H.T.); and Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (Y.W., T.I.)
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Hiroaki Tominaga
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan (Y.W., M.K., K.S., A.N., K.T., H.T.); Research and Development Department, Kotobuki Pharmaceutical Co., Ltd., Nagano, Japan (H.T.); and Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (Y.W., T.I.)
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Hiroshi Tomiyama
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan (Y.W., M.K., K.S., A.N., K.T., H.T.); Research and Development Department, Kotobuki Pharmaceutical Co., Ltd., Nagano, Japan (H.T.); and Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (Y.W., T.I.)
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Tomohisa Ishikawa
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan (Y.W., M.K., K.S., A.N., K.T., H.T.); Research and Development Department, Kotobuki Pharmaceutical Co., Ltd., Nagano, Japan (H.T.); and Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (Y.W., T.I.)
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Abstract

Renal inflammation is a final common pathway of chronic kidney disease (CKD), and its progression can be used to effectively gauge the degree of renal dysfunction. Inflammatory mechanisms contribute to glomerulosclerosis and tubulointerstitial fibrosis, which are hallmarks of CKD leading to end-stage renal disease. Receptor-interacting protein kinase 2 (RIP2) is largely committed to nucleotide-binding oligomerization domain signaling as a direct effector and transmits nuclear factor-κB (NF-κB)–mediated proinflammatory cytokine production. In the present study, we hypothesized that if inflammation via RIP2 and NF-κB signaling plays an important role in renal failure, then the anti-inflammatory effect of RIP2 inhibitors should be effective in improving CKD. To determine its pharmacologic potency, we investigated the renoprotective properties of the novel RIP2 inhibitor AS3334034 [7-methoxy-6-(2-methylpropane-2-sulfonyl)-N-(4-methyl-1H-pyrazol-3-yl)quinolin-4-amine] in uninephrectomized adriamycin-induced CKD rats. Six weeks’ repeated administration of AS3334034 (10 mg/kg, once daily) significantly reduced urinary protein excretion and prevented the development of glomerulosclerosis and tubulointerstitial fibrosis. In addition, AS3334034 showed beneficial effects on renal function, as demonstrated by a decrease in levels of plasma creatinine and blood urea nitrogen and attenuation of a decline in creatinine clearance. Furthermore, AS3334034 significantly attenuated inflammation, renal apoptosis, and glomerular podocyte loss. These results suggest that the RIP2 inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect and is therefore potentially useful in treating patients with CKD.

SIGNIFICANCE STATEMENT The receptor-interacting protein kinase 2 (RIP2) inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect, suggesting that the nucleotide-binding oligomerization domain–RIP2 axis might play a crucial role in the pathogenesis of inflammatory kidney diseases. AS3334034 is expected to be potentially useful in the treatment of patients with chronic kidney disease.

Footnotes

    • Received February 18, 2020.
    • Accepted June 12, 2020.
  • Y.W., M.K., K.S., A.N., K.T., and H.T. are employees of Astellas Pharma Inc. The study was funded by Astellas Pharma Inc.

  • https://doi.org/10.1124/jpet.120.265678.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 374 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 374, Issue 3
1 Sep 2020
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Renoprotective Effects of AS3334034 in CKD Rats

Yusuke Wada, Mitsuhiro Kondo, Kumi Sakairi, Akira Nagashima, Kenichi Tokita, Hiroaki Tominaga, Hiroshi Tomiyama and Tomohisa Ishikawa
Journal of Pharmacology and Experimental Therapeutics September 1, 2020, 374 (3) 428-437; DOI: https://doi.org/10.1124/jpet.120.265678

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Renoprotective Effects of AS3334034 in CKD Rats

Yusuke Wada, Mitsuhiro Kondo, Kumi Sakairi, Akira Nagashima, Kenichi Tokita, Hiroaki Tominaga, Hiroshi Tomiyama and Tomohisa Ishikawa
Journal of Pharmacology and Experimental Therapeutics September 1, 2020, 374 (3) 428-437; DOI: https://doi.org/10.1124/jpet.120.265678
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