Inhibition of tumor necrosis factor-α enhanced the antifibrotic effect of empagliflozin in an animal model with renal insulin resistance

Abstract

Insulin resistance (IR) has emerged as one of the main risk factors for renal fibrosis (RF) that represents a common stage in almost all chronic kidney disease. The present study aims to investigate the inhibitory effect of empagliflozin (EMPA "a sodium-glucose co-transporter 2 inhibitor") and infliximab [IFX "a tumor necrosis factor-α (TNF-α) antibody"] on RF in rats with induced IR. IR was induced by adding 10% fructose in drinking water for 20 weeks. Thereafter, fructose-induced IR rats were concurrently treated with EMPA (30 mg/kg), IFX (1 dose 5 mg/kg), or EMPA + IFX for 4 weeks, in addition to IR control group (received 10% fructose in water) and normal control (NC) group. Rats with IR displayed hyperglycemia, deterioration in kidney functions, glomerulosclerosis, and collagen fiber deposition in renal tissues as compared to NC. This was associated with downregulation of the renal sirtuin 1 (Sirt 1) expression along with higher renal tissue TNF-α and transforming growth factor-β1 (TGF-β1) levels. Both EMPA and IFX significantly modulated the aforementioned fibrotic cytokines, upregulated the renal Sirt 1 expression, and attenuated RF compared to IR control group. Of note, IFX effect was superior to that of EMPA. However, the combination of EMPA and IFX alleviated RF to a greater extent surpassing the monotherapy. This may be attributed to the further upregulation of renal Sirt 1 in addition to the downregulation of fibrotic cytokines. These findings suggest that the combination of EMPA and IFX offers additional benefits and may represent a promising therapeutic option for RF.

Review on Inflammation Markers in Chronic Kidney Disease

“…Nonetheless, their use in patients with rheumatoid arthritis from the KOBIO registry did not influence any change in renal function [77]. Furthermore, a study on rats has shown that a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and infliximab prevented renal fibrosis to a greater extent than monotherapy, which could present a promising therapeutic option [78].…”

Diabetic Nephropathy Progression in type 1 Diabetes: Temporal Renal Angiopoietin-Like Protein 2-Toll-Like Receptor 4 and Role of Early Renal Angiotensin II Inhibition by Valsartan

“…DN has early glomerular barrier and tubular dysfunction component [4,52]. Early in diabetes, the hemodynamic changes involve efferent arteriolar vasoconstriction in contrast to afferent vasodilation that ultimately increases glomerular hydrostatic pressure [17], leading to glomerular hyper ltration in diabetes [53].…”

“…The present study demonstrates long-term ARB inhibition in an animal model of T1D, which can delay and decrease the development of diabetic glomerulopathy, by modulating glomerular diabetes-associated hemodynamic changes. Further studies are needed to weight hemodynamic versus non-hemodynamic [12,52] factors that predominate in the pathophysiology and pathogenesis of DN in clinical practice and the starting time of ARB initiation.…”

Empagliflozin therapy and insulin resistance-associated disorders: effects and promises beyond a diabetic state

“…An interesting study explored the possible effect of empagliflozin and infliximab, both as monotherapy and combination therapy, to rats with renal fibrosis and induced IR [ 62 ]. Thirty male Wistar albino rats were fed either with an NC diet ( n = 6, NC controls) or fructose-based diet so as to induce IR ( n = 24).…”