Abstract P330: Role of Na-H Exchanger Regulatory Factor 1 (NHERF1) In Salt-sensitive Hypertension and Inflammation in Aging

Abstract

Aging animals develop salt-sensitive hypertension due, in part, to desensitization of dopamine receptors and sensitization of AT1R in renal proximal tubules. We demonstrated old FBN rats develop salt-dependent hypertension. Preliminary data showed loss of NHERF1 expression in 22m old F344 rats. We hypothesized that loss of NHERF1 may contribute to salt reabsorption in aging. To address this hypothesis, Fischer Brown Norway (FBN) rats (1m, 4m, 12m, and 24m old) were fed 1% or 8% NaCl diet for one week and, urinary volume, sodium, potassium, and chloride and expression of Na-K ATPase α1 subunit (NKA), NHERF1, and D1R were measured. Feeding 8% NaCl increased 24 h urine volume compared to rats fed 1% NaCl diet in 1m (13.6±0.98 vs 29.2±3.8 mL) and 4m (15.3±1.5 vs 39.2±2.4) but not in 24 m rats (20.7±4.7 vs 15.9±2.4). 24 h urine Na increased 7 fold in 4 m old rats fed an 8% NaCl diet but only 3 fold in 24m old rats. To our surprise, NHERF1 expression increased with age in FBN rats (0.21±.03 (4m) vs 0.71±0.07 (24m) AU ratio NHERF1:actin). In F344 rats NHERF1 expression decreased with age (0.86±0.14 vs 0.39±0.05). Increased NHERF1 expression with age in FBN rats was associated with decreased D1R expression (0.8±0.16 vs 0.4±0.04) while in F344 rats D1R expression increased with age (0.6±0.1 vs 0.9±0.1). FBN rats are salt-sensitive while F344 are salt-resistant. F344 rats develop kidney inflammation with aging. We determined TNFα in kidney homogenates from FBN and F344 rats. TNFα increased with age in both F344 (4.04±0.15 vs 6.9±0.42) and FBN rats (2.1±0.3 vs 4.05±0.31 ng/mg protein). To determine if lack of NHERF1 is responsible for salt wasting, we measured urine volume and Na in 18 m old WT and NHERF1 KO mice. The urine volume in WT mice (2.7±0.8 (1% NaCl) vs 5.6±1.2 mL/24 h (8% NaCl)) were significantly lower than KO mice (3.6±0.57(1% NaCl) vs 7.5±0.88 mL/24 h (8% NaCl)). Similar results were observed in Na excretion. D1R expression increased in NHERF1 KO mice as compared to WT mice. TNFα increased significantly in NHERF1 KO mice kidneys as compared to WT mice. We conclude that increased NHERF1 expression as seen in FBN rats results in salt retention while lack of NHERF1 as seen F344 rats and NHERF1 KO mice increases renal inflammation. Further studies are required to delineate the two roles of NHERF1.