HIF Stabilizer Desidustat Protects against Complement-Mediated Diseases.

Autor:	Patel VJ; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India., Joharapurkar AA; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India., Kshirsagar SG; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India., Patel MS; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India., Savsani HH; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India., Dodiya HS; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India., Rakhasiya MH; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India., Patel AK; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India., Sundar R; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India., Jain MR; Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India.
Jazyk:	angličtina
Zdroj:	Drug research [Drug Res (Stuttg)] 2024 Sep; Vol. 74 (7), pp. 325-334. Date of Electronic Publication: 2024 Jul 11.
DOI:	10.1055/a-2347-9919
Abstrakt:	Complement cascade is a defence mechanism useful for eliminating pathogenic microorganisms and damaged cells. However, activation of alternative complement system can also cause inflammation and promote kidney and retinal disease progression. Inflammation causes tissue hypoxia, which induces hypoxia-inducible factor (HIF) and HIF helps the body to adapt to inflammation. In this study, we investigated the effect of HIF stabilizer desidustat in complement-mediated diseases. Oral administration of desidustat (15 mg/kg) was effective to reduce the kidney injury in mice that was induced by either lipopolysaccharide (LPS), doxorubicin or bovine serum albumin (BSA)-overload. Complement activation-induced membrane attack complex (MAC) formation and factor B activity were also reduced by desidustat treatment. In addition, desidustat was effective against membranous nephropathy caused by cationic BSA and retinal degeneration induced by sodium iodate in mice. C3-deposition, proteinuria, malondialdehyde, and interleukin-1ß were decreased and superoxide dismutase was increased by desidustat treatment in cBSA-induced membranous nephropathy. Desidustat specifically inhibited alternative complement system, without affecting the lectin-, or classical complement pathway. This effect appears to be mediated by inhibition of factor B. These data demonstrate the potential therapeutic value of HIF stabilization by desidustat in treatment of complement-mediated diseases. Competing Interests: All the authors are employees of Zydus Research Centre, Zydus Lifesciences Limited, Ahmedabad, India. No author of this manuscript has any potential competing interest. (Thieme. All rights reserved.)
Databáze:	MEDLINE
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