Chronic Nf-κB Inhibition Prevents Experimental Aging Nephropathy.

Abstract

Introduction The pathogenesis of aging nephropathy is yet to be elucidated. Intrarenal Angiotensin-II (AngII) and activation of the NF-κB and NLRP3 inflammasome pathways exert a relevant pathogenic role in the progression of chronic kidney disease (CKD). We sought to investigate whether monotherapy with Losartan and combined treatment with Losartan and the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) would attenuate experimental aging nephropathy. 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/conclusion 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.