Early Renoprotective Effect of Ruxolitinib in a Rat Model of Diabetic Nephropathy.

Mohamed M El-Kady,Maha Guimei,Iman M Talaat,Reham A Naggar,Maha Saber-Ayad,Olfat G Shaker

doi:10.3390/ph14070608

Abstract

Diabetic kidney disease (DKD) is still one of the unresolved major complications of diabetes mellitus, which leads ultimately to end-stage renal disease in both type 1 and type 2 diabetes patients. Available drugs that suppress the renin–angiotensin system have partially minimized the disease impact. Yet, there is an unmet need for new therapeutic interventions to protect the kidneys of diabetic patients. In DN, glomerular sclerosis and tubulointerstitial fibrosis are mediated through several pathways, of which JAK/STAT is a key one. The current study explored the potential renoprotective effect of the JAK1/JAK2 inhibitor ruxolitinib (at doses of 0.44, 2.2, and 4.4 mg·kg−1) compared to that of enalapril at a dose of 10 mg·kg−1, in a rat model of streptozotocin-induced diabetes mellitus over 8 weeks. The effect of ruxolitinib was assessed by determining urinary albumin/creatinine ratio, serum level of cystatin, and levels of TGF-β1, NF-κB, and TNF-α in renal tissue homogenates by biochemical assays, the glomerular sclerosis and tubulointerstitial fibrosis scores by histological analysis, and fibronectin, TGF-β1, and Vimentin levels by immunohistochemical staining with the respective antibodies. Our results revealed a significant early favorable effect of a two-week ruxolitinib treatment on the renal function, supported by a decline in the proinflammatory biomarkers of DKD. This pre-clinical study suggests that the renoprotective effect of ruxolitinib in the long term should be investigated in animals, as this drug may prove to be a potential option for the treatment of diabetic kidney disease.

Highlights

IntroductionDiabetes mellitus is the major cause of end-stage renal disease (ESRD) all over the world
Renal tissue proinflammatory biomarkers, and histopathological changes, our findings show a favorable effect of ruxolitinib in the rat model of Diabetic kidney disease (DKD)
Activated Janus kinase (JAK) phosphorylate STAT proteins, which translocate to the nucleus to induce target gene transcription of a variety of cytokines, adhesion molecules, growth factors, extracellular matrix proteins, pro-oxidant enzymes, and scavenger receptors, leading to several pathologies related to DKD, including inflammation, oxidative stress, lipotoxicity and fibrosis [38,39]

Summary

Introduction

Diabetes mellitus is the major cause of end-stage renal disease (ESRD) all over the world. The global percentage of diabetes patients with ESRD has increased to around. 47% of ESRD cases in the United States are due to diabetic nephropathy [2]. A good control of diabetes positively impacts the natural course of the disease, as shown by a decline in the rate of worsening of albuminuria and of plasma creatinine levels; renal dialysis or transplantation remains, the ultimate outcome [3]

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