Role of Sodium Hydrogen Exchange Regulatory Factor‐1 (NHERF1) in Aging: Tale of Two Rat Models

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 22mo 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 (1, 4, 12, and 24mo old) were fed 1% or 8% NaCl diet for one week and, urinary volume, sodium, potassium, and chloride and expression of Na‐K ATPase a1 subunit (NKA), NHERF1, NKCC2, NCC, and D1R were measured. Feeding 8% NaCl increased 24 h urine volume compared to rats fed 1% NaCl diet in 1mo (13.6±0.98 vs 29.2±3.8 mL) and 4mo (15.3±1.5 vs 39.2±2.4) but not in 24 mo rats (20.7±4.7 vs 15.9±2.4). U Na V and U Cl V increased in young rats fed with 8% NaCl but not in old rats. U K V did not change in young rats but significantly decreased in older rats. To our surprise, in contrast to F344 rats, NHERF1 expression increased with age in FBN rats (0.21±.03 (4mo) vs 0.71±0.07 (24mo) AU ratio NHERF1:actin). 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). To determine the role of NHERF1 in the two models of rats, we determined TNFa in kidney homogenates from FBN and F344 rats. TNFa increased with age in both F344 (4.04±0.15 (4 mo) vs 6.9±0.42 (24 mo)) and FBN rats (2.1±0.3 vs 4.05±0.31 ng/mg protein). TNFa levels were significantly higher in young F344 rats as compared to young FBN rats. To determine if lack of NHERF1 is responsible for salt wasting, we measured urine volume and Na in 18 mo 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)). However, there was no significant difference in UNaV between WT and KO mice fed an 8% NaCl diet. D1R expression increased in NHERF1 KO mice as compared to WT mice. TNFa increased significantly in NHERF1 KO mice kidneys as compared to WT mice. We conclude that increased NHERF1 expression as seen in FBN rats result 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. Support or Funding Information NIA grants R21AG047474 and R25AG047843 and AHA grant 16GRNT31030019