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- Title
Prolyl hydroxylase inhibitor desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines and oxidative stress.
- Authors
Joharapurkar, Amit A.; Patel, Vishal J.; Kshirsagar, Samadhan G.; Patel, Maulik S.; Savsani, Hardikkumar H.; Jain, Mukul R.
- Abstract
Chronic kidney disease (CKD) is associated with activated inflammatory responses. Desidustat, a prolyl hydroxylase (PHD) inhibitor is useful for treatment of anemia associated with CKD, but its effect on the inflammatory and fibrotic changes in CKD is not evaluated. In this study, we investigated the effect of desidustat on the inflammatory and fibrotic changes in preclinical models of acute and chronic kidney injury. Acute kidney injury was induced in male Sprague Dawley rats by ischemia–reperfusion, in which effect of desidustat (15 mg/kg, PO) was estimated. In a separate experiment, male C57 mice were treated with adenine for 14 days to induce CKD. These mice were treated with desidustat (15 mg/kg, PO, alternate day) treatment for 14 days, with adenine continued. Desidustat prevented elevation of serum creatinine, urea, IL‐1β, IL‐6, and kidney injury molecule‐1 (KIM‐1), and elevated the erythropoietin levels in rats that were subjected to acute kidney injury. Mice treated with adenine developed CKD and anemia, and desidustat treatment caused improvement in serum creatinine, urea, and also improved hemoglobin and reduced hepatic and serum hepcidin. A significant reduction in IL‐1β, IL‐6, myeloperoxidase (MPO) and oxidative stress was observed by desidustat treatment. Desidustat treatment also reduced renal fibrosis as observed by histological analysis and hydroxyproline content. Desidustat treatment reduced the renal fibrosis and inflammation along with a reduction in anemia in preclinical models of kidney injury, which may translate to protective effects in CKD patients.
- Subjects
ACUTE kidney failure; ADENINE; RENAL fibrosis; OXIDATIVE stress; SPRAGUE Dawley rats; CHRONIC kidney failure; UREA
- Publication
Drug Development Research, 2021, Vol 82, Issue 6, p852
- ISSN
0272-4391
- Publication type
Article
- DOI
10.1002/ddr.21792