Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is a multifactorial disease characterized by hyperglycemia and close interaction of hemodynamic, metabolic and inflammatory factors. Nuclear factor-κB (NF-κB) is a principal matchmaker linking hyperglycemia and inflammation. The present work investigates the cell-permeable peptide containing the inhibitor of kappa B kinase γ (IKKγ)/NF-κB essential modulator (NEMO)-binding domain (NBD) as therapeutic option to modulate inflammation in a preclinical model of type 2 diabetes (T2D) with DN. Black and tan, brachyuric obese/obese mice were randomized into 4 interventions groups: Active NBD peptide (10 and 6 µg/g body weight); Inactive mutant peptide (10 µg/g); and vehicle control. In vivo/ex vivo fluorescence imaging revealed efficient delivery of NBD peptide, systemic biodistribution and selective renal metabolization. In vivo administration of active NBD peptide improved albuminuria (>40% reduction on average) and kidney damage, decreased podocyte loss and basement membrane thickness, and modulated the expression of proinflammatory and oxidative stress markers. In vitro, NBD blocked IKK-mediated NF-κB induction and target gene expression in mesangial cells exposed to diabetic-like milieu. These results constitute the first nephroprotective effect of NBD peptide in a T2D mouse model that recapitulates the kidney lesions observed in DN patients. Targeting IKK-dependent NF-κB activation could be a therapeutic strategy to combat kidney inflammation in DN.

Relationships of the Trace Elements Zinc and Magnesium With Diabetic Nephropathy-Associated Renal Functional Damage in Patients With Type 2 Diabetes Mellitus

“…Previous studies have also shown that Zn administration reduces NF-κB activation and ameliorates vascular endothelial cell dysfunction ( 25 ). NF-κB is an important pro-inflammatory mediator in patients with DN, with its activation resulting in the production of a variety of pro-inflammatory cytokines, the proliferation, and hypertrophy of mesangial cells, and tubulointerstitial fibrosis ( 26 ). Specifically, NF-κB activation results in greater release of TNF-α, IL-6, and IL-8, and in turn, TNF-α increases the production of IL-1, IL-6, IL-8, and IL-18 ( 27 ).…”

Targeted drug delivery strategy: a bridge to the therapy of diabetic kidney disease

“…NF-κB is a bridge linking inflammation and hyperglycemia. A Cell-permeable peptide, designing with the inhibitor of kappa B kinase γ (IKKγ)/NF-κB essential modulator (NEMO)-binding domain (NBD), alleviates the albuminuria, kidney damage, podocyte loss and GBM thickness in DKD rat models (Opazo-Rios et al., 2020 ).…”

Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

“…Persistent hyperglycemia causes inflammation, endothelial dysfunction, and oxidative stress in the kidneys and, thus, is partly associated with DKD progression [ 8 , 9 , 10 ]. In addition to traditional hypoglycemic agents and insulin, several agents targeting peptidyl hormones, such as dipeptidyl peptide IV and glucagon-like peptide-1, have recently been introduced for the treatment of hyperglycemia [ 11 ].…”