Chronic Nuclear Factor-Kappa B Inhibition Prevents Experimental Aging Nephropathy

Introduction: The pathogenesis of aging nephropathy (AN) is yet to be elucidated. Intrarenal angiotensin II (AngII) and activation of the nuclear factor-kappa B (NF-κB) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathways exert a relevant pathogenic role in the progression of chronic kidney disease. We sought to investigate whether monotherapy with losartan and combined treatment with losartan and the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) would attenuate experimental AN.

Materials and methods: Forty adult male Munich-Wistar rats were distributed among four groups: 12M (n = 10), untreated 12-month-old rats; 15M (n = 10), untreated 15-month-old rats; 15MLos (n = 8), rats receiving losartan (50 mg/kg/d); and 15MLos+PDTC (n = 8), rats receiving losartan and PDTC (60 mg/kg/d). All treatments were given by mouth from 12 to 15 months of age.

Results: Group 15M exhibited slightly decreased tail-cuff pressure and marked increase in albuminuria, sclerotic glomeruli, cortical collagen-1 deposition and infiltration by myofibroblasts, AngII-positive cells, and proinflammatory M1 macrophages, whereas the amount of anti-inflammatory M2 macrophages was reduced. In addition, the renal abundance of TLR4, nuclear p65, and IL-6 was increased, indicating activation of the NF-κB pathway, without evidence of simultaneous activation of the NLRP3 cascade. Losartan treatment decreased cortical collagen-1 deposition, myofibroblasts, and AngII-positive cells and partially restored renal M2 but had no significant effect on albuminuria, glomerulosclerosis, or NF-κB activation. Combined losartan+PDTC prevented all the observed abnormalities.

Discussion: Simultaneous blockade of renal AngII and inhibition of the NF-κB pathway may represent a novel alternative to limit the decline of renal function with age.