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

Author(s):Show less -

Foresto-Neto, Orestes ^[1] ; Albino, Amanda Helen ^[1] ; Arias, Simone Costa Alarcon ^[1] ; Faustino, Viviane Dias ^[1] ; Zambom, Fernanda Florencia Fregnan ^[1] ; Cenedeze, Marcos Antonio ^[2] ; Elias, Rosilene Motta ^[1] ; Malheiros, Denise Maria Avancini Costa ^[1] ; Camara, Niels Olsen Saraiva ^{[2, 1]} ; Fujihara, Clarice Kazue ^[1] ; Zatz, Roberto ^[1]

Affiliation

^[1] Univ Sao Paulo, Div Renal, Dept Clin Med, Fac Med, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Div Nephrol, Dept Med, Sao Paulo - Brazil

• Document type: Journal article
• Source: FRONTIERS IN PHYSIOLOGY; v. 11, FEB 11 2020.
• Web of Science Citations: 0

Abstract

High glucose concentration can activate TLR4 and NF-kappa B, triggering the production of proinflammatory mediators. We investigated whether the NF-kappa B 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-kappa B 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-kappa B inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented activation of renal TLR4, NF-kappa B 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-kappa B 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-kappa B 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 Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 12/10926-5 - Pathogenesis and treatment of chronic kidney disease: role of innate immunity in glomerular, tubular and interstitial injury
• Grantee: Roberto Zatz
• Support Opportunities: Research Projects - Thematic Grants