NF-kappa B activation promotes glomerular injury and inflammation in experimental diabetic kidney

Author(s)

Orestes Foresto Neto

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina
• Defense date: 21 jan. 2019

Examining board members

Roberto Zatz; Hugo Abensur; Mirian Aparecida Boim; Niels Olsen Saraiva Câmara

• Advisor: Roberto Zatz

Abstract

High glucose concentration can activate the TLR4/NF-kB axis, triggering the production of proinflammatory mediators. We investigated whether the NF-kB 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). 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 nonprogressors - could be formed based on the degree of glomerulosclerosis. Only the progressors exhibited renal TLR4/NF-kB/IL-6 activation. This scenario was already present in rats with short-term DM (two months), at a time when no albuminuria or overt glomerulosclerosis can be detected. Chronic treatment with the NF-kB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented the renal TLR4/NF-kB/IL-6 activation, while exerting no interference on blood glucose. PDTC abrogated the increase in albuminuria, prevented the development of glomerular injury/inflammation and oxidative stress in DM rats. In addition, the NF-kB 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-kB 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 (AU)

• FAPESP's process: 13/12256-0 - The role of innate immunity in pathogenesis of diabetic nephropathy
• Grantee: Orestes Foresto Neto
• Support type: Scholarships in Brazil - Doctorate (Direct)