Abstract 117: NOS1β Mediates the Difference Between Juxtamedullary and Superficial Glomerular Injury with Aging

Abstract

Renal function measured by glomerular filtration rate (GFR) declines with aging. But the mechanism has not been clarified. Nitric oxide synthase 1 β (NOS1β) is highly expressed in the macula densa (MD) and modulates tubuloglomerular feedback (TGF), which is an important mechanism for GFR regulation. We hypothesized that expression of NOS1β in MD decreases with aging, which enhances TGF response and contributes to the decline of GFR. We further hypothesized that NOS1β expression in superficial (SF) MD is lower than that of juxtamedullary (JM) MD, which contribute to more severe renal injury in renal cortex with aging. First, GFR was measured by plasma FITC-inulin clearance after a single bolus injection in conscious 12-week young mice and 20-month-old C57/BL6 mice. GFR was reduced by 36.4% in aged mice (236±9.7 vs 150±7.6 μl/min). Then we compared the glomerular injury in 20-month-old C57/BL6 mice with 12-week mice. The aged mice have significant severed injury compared to the young mice as indicated by injury scores (3.6) and expanded fractional mesangial area (FMA) per glomerulus (26.4%). In addition, injuries were more evident in SF glomeruli with larger FMA (29.3%) than that in JM glomeruli (16.9%). Next we measured NOS1β protein abundance and found that NOS1β protein in aged mice was reduced by 73% compared to young mice. In addition, we compared the NOS1β abundance between SF and JM glomeruli in aged and young mice. NOS1β protein level decreased by more than 90% in SF nephrons in aged mice compared with the young mice. In contrast, there was no significant changes in NOS1β expression in JM nephron between aged and young mice. To determine whether NOS1β mediates the changes in GFR and renal injury, we repeated the experiments in age matched MD specific NOS1β knock out (MD-NOS1KO) mice. In MD-NOS1KO mice, GFR in aged mice was reduced by 29.5% (203±15.7 vs 143±13.2 μl/min) compared young mice. Aged MD-NOS1KO mice had more severer renal injury compared with age-match wild type mice with higher injury score (4.7 vs 3.6), increased FMA (40.9% vs 26.4%) and occurrence of glomerulosclerosis (GS 30.8% ), but diminished difference between JM glomerulus (FMA37.4%, GS34.1%) and SF glomerulus (FMA42.2%, GS29.7%).