NF-κB System Is Chronically Activated and Promotes Glomerular Injury in Experimental Type 1 Diabetic Kidney Disease.

Orestes Foresto-Neto,Niels Olsen Saraiva Camara,Roberto Zatz,Fernanda Florencia Fregnan Zambom,Viviane Dias Faustino,Rosilene Motta Elias,Amanda Helen Albino,Clarice Kazue Fujihara,Simone Costa Alarcon Arias,Denise Maria Avancini Costa Malheiros,Marcos Antonio Cenedeze

doi:10.3389/fphys.2020.00084

Orestes Foresto-Neto, Niels Olsen Saraiva Camara + Show 9 more

Open Access

https://doi.org/10.3389/fphys.2020.00084

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Abstract

High glucose concentration can activate TLR4 and NF-κB, triggering the production of proinflammatory mediators. We investigated whether the NF-κB pathway is involved in the pathogenesis and progression of experimental diabetic kidney disease (DKD) in a model of long-term type 1 diabetes mellitus (DM). Adult male Munich-Wistar rats underwent DM by a single streptozotocin injection, and were kept moderately hyperglycemic by daily insulin injections. After 12 months, two subgroups – progressors and non-progressors – could be formed based on the degree of glomerulosclerosis. Only progressors exhibited renal TLR4, NF-κB and IL-6 activation. This scenario was already present in rats with short-term DM (2 months), at a time when no overt glomerulosclerosis can be detected. Chronic treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented activation of renal TLR4, NF-κB or IL-6, without interfering with blood glucose. PDTC prevented the development of glomerular injury/inflammation and oxidative stress in DM rats. In addition, the NF-κB p65 component was detected in sclerotic glomeruli and inflamed interstitial areas in biopsy material from patients with type 1 DM. These observations indicate that the renal NF-κB pathway plays a key role in the development and progression of experimental DKD, and can become an important therapeutic target in the quest to prevent the progression of human DKD.

Highlights

The pathogenesis of Diabetic Kidney Disease (DKD) remains elusive, despite the advancements obtained in the past few decades
As expected, %GS and macrophage infiltration were significantly increased in Group diabetic kidney disease (DKD)+ compared with DKD− (Figures 2B–D)
These changes were associated with an increased renal content of TLR4, nuclear p65 and IL-6, whereas the renal content of NLRP3 was not changed (Figures 3A–F)

Summary

Introduction

The pathogenesis of Diabetic Kidney Disease (DKD) remains elusive, despite the advancements obtained in the past few decades. Since DKD remains a leading cause of chronic kidney disease (CKD), the development of novel therapeutic strategies is badly needed. The nuclear factor kappa B (NF-κB) cascade was shown to be set off in rats with 5/6ths renal ablation or adenine overload, whereas NF-κB inhibition with pyrrolidine dithiocarbamate (PDTC) was shown to prevent the development of renal injury in these CKD models (Fujihara et al, 2007; Okabe et al, 2013). A previous study of STZ-diabetic rats demonstrated activation of the renal NF-κB system, and showed that treatment with PDTC reverted renal inflammation at an early phase (Lee et al, 2004). The possibility that PDTC may prevent the long-term development of glomerulosclerosis was not verified in that study

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