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.

Lucas Opazo-Ríos,Sergio Mezzano,Anita Plaza,Daniel Carpio,Carmen Gomez-Guerrero,Yenniffer Sánchez Matus,Jesús Egido,Luna Jimenez-Castilla,Susana Bernal,Laura Lopez-Sanz,Alejandra Droguett

doi:10.3390/ijms21124225

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.

Highlights

Type 2 diabetes (T2D) is one of the biggest problems in global public health and considered a pandemic problem both in emerging nations and industrialized countries [1,2]
In T2D, chronic hyperglycemia, salt-sensitive hypertension and obesity produce metabolic, hemodynamic and lipotoxic effects described as main activators of intracellular signaling pathways such as nuclear factor kappa–B (NF-κB), Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and nuclear factor erythroid 2-related factor 2/heme-oxigenase-1(Nrf2/Hmox-1) [9,10,11,12]
Activation of proinflammatory Nuclear factor-κB (NF-κB) pathway has been revealed as a key molecular system involved in pathologic induction of kidney inflammation during diabetic nephropathy (DN) [7,8]

Summary

Introduction

Type 2 diabetes (T2D) is one of the biggest problems in global public health and considered a pandemic problem both in emerging nations and industrialized countries [1,2]. Sodium-glucose transport protein 2 inhibitors and glucagon like-peptide receptors agonist allow better metabolic control in these patients, diabetic nephropathy (DN) remains the main cause of end-stage renal disease worldwide [3,4]. Novel anti-inflammatory therapeutic strategies could be proposed, especially in patients with rapidly progressive phenotypes such as genetic susceptibility, extreme obesity, poor metabolic control and concomitant inflammatory disease, among others [5,6]. In T2D, chronic hyperglycemia, salt-sensitive hypertension and obesity produce metabolic, hemodynamic and lipotoxic effects described as main activators of intracellular signaling pathways such as nuclear factor kappa–B (NF-κB), Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and nuclear factor erythroid 2-related factor 2/heme-oxigenase-1(Nrf2/Hmox-1) [9,10,11,12]. Activation of proinflammatory NF-κB pathway has been revealed as a key molecular system involved in pathologic induction of kidney inflammation during DN [7,8]

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Conclusion