Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria

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Faustino, Viviane Dias ; Alarcon Arias, Simone Costa ; Avila, Victor Ferreira ; Foresto-Neto, Orestes ; Fregnan Zambom, Fernanda Florencia ; Machado, Flavia Gomes ; dos Reis, Luciene Machado ; Maria, Denise ; Malheiros, Avancini Costa ; Volpini, Rildo Aparecido ; Saraiva Camara, Niels Olsen ; Zatz, Roberto ; Fujihara, Clarice Kazue

• Tipo de documento: Artigo Científico
• Fonte: BIOSCIENCE REPORTS; v. 38, p. 18-pg., 2018-08-31.

Resumo

Protein overload of proximal tubular cells (PTCs) can promote interstitial injury by unclear mechanisms that may involve activation of innate immunity. We investigated whether prolonged exposure of tubular cells to high protein concentrations stimulates innate immunity, triggering progressive interstitial inflammation and renal injury, and whether specific inhibition of innate or adaptive immunity would provide renoprotection in an established model of massive proteinuria, adriamycin nephropathy (ADR). Adult male Munich-Wistar rats received a single dose of ADR (5 mg/kg, iv), being followed for 2, 4, or 20 weeks. Massive albuminuria was associated with early activation of both the NE-kappa B and NLRP3 innate immunity pathways, whose intensity correlated strongly with the density of lymphocyte infiltration. In addition, ADR rats exhibited clear signs of renal oxidative stress. Twenty weeks after ADR administration, marked interstitial fibrosis, glomerulosclerosis, and renal functional loss were observed. Administration of mycophenolate mofetil (MMF), 10 mg/kg/day, prevented activation of both innate and adaptive immunity, as well as renal oxidative stress and renal fibrosis. Moreover, MMF treatment was associated with shifting of M from the M1 to the M2 phenotype. In cultivated NRK52-E cells, excess albumin increased the protein content of Toll-like receptor (TLR) 4 (TLR4), NLRP3, MCP-1, IL6, IL-1 beta Caspase-1, alpha-actin, and collagen-1. Silencing of TLR4 and/or NLRP3 mRNA abrogated this proinflammatory/profibrotic behavior. Simultaneous activation of innate and adaptive immunity may be key to the development of renal injury in heavy proteinuric disease. Inhibition of specific components of innate and/or adaptive immunity may be the basis for future strategies to prevent chronic kidney disease (CKD) in this setting. (AU)

• Processo FAPESP: 13/11929-0 - Efeito de uma disfunção da barreira glomerular sobre a imunidade inata de células tubulares proximais
• Beneficiário: Viviane Dias Faustino
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/10926-5 - Patogênese e terapêutica da doença renal crônica: papel da imunidade inata na lesão de glomérulos, túbulos e interstício
• Beneficiário: Roberto Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Temático