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Therapeutic effects of interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 on diabetic nephropathy in type 2 diabetic mice

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Abstract

Renal inflammation is a final common pathway of chronic kidney disease including diabetic nephropathy, which is the leading cause of end-stage renal disease and is associated with high cardiovascular risk and significant morbidity and mortality. Interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4) is a pivotal molecule for IL-1 receptor- and Toll-like receptor-induced activation of proinflammatory mediators. In this study, we investigated the renoprotective properties of IRAK-4 inhibitor AS2444697 in KK/Ay type 2 diabetic mice. Four-week repeated administration of AS2444697 dose-dependently and significantly improved albuminuria; hyperfiltration, as measured by creatinine clearance; renal injury, including glomerulosclerosis; tubular injury markers, including urinary N-acetyl-β-D-glucosaminidase activity; and glomerular podocyte injury markers, including urinary nephrin excretion. In addition, AS2444697 attenuated plasma levels of proinflammatory cytokines, including IL-6; plasma levels of endothelial dysfunction markers, including intercellular adhesion molecule-1; and plasma levels and renal contents of oxidative stress markers. In contrast, AS2444697 did not significantly affect food intake or blood glucose levels. These results suggest that AS2444697 attenuates the progression of diabetic nephropathy mainly via anti-inflammatory mechanisms through inhibition of IRAK-4 activity under diabetic conditions and may represent a promising therapeutic option for the treatment of type 2 diabetic nephropathy.

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Acknowledgements

The authors thank Drs. Masaki Abe and Hiroyuki Ito (Astellas Pharma Inc.) for their valuable comments and continuing encouragement.

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Authors and Affiliations

  1. Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan

    Mitsuhiro Kondo, Atsuo Tahara, Kazumi Hayashi, Hiroshi Inami, Takeshi Ishikawa & Yuichi Tomura

Authors
  1. Mitsuhiro Kondo
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  2. Atsuo Tahara
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  3. Kazumi Hayashi
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  4. Hiroshi Inami
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  5. Takeshi Ishikawa
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  6. Yuichi Tomura
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Contributions

MK, AT, KH, HI, and TI conceived and designed the research. MK and AT performed experiments and analyzed the data. MK, AT, and YT wrote the manuscript. All authors read and approved the manuscript.

Corresponding author

Correspondence to Atsuo Tahara.

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Animal studies were approved by the Institutional Animal Care and Use Committee of Astellas Pharma Inc., Tsukuba Research Center, which is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International.

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The authors declare that they have no conflict of interest.

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Kondo, M., Tahara, A., Hayashi, K. et al. Therapeutic effects of interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 on diabetic nephropathy in type 2 diabetic mice. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1197–1209 (2020). https://doi.org/10.1007/s00210-020-01816-2

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