Glomerular hypertension and hyperfiltration in young fvb.ROP Os/+ mice

Abstract

ROP Os+/− mice, generated by a radiation-induced 10 Mb DNA inversion of chromosome 8 and resulting in an oligosyndactyly (Os) allele, have a 50% reduction in nephron number and develop glomerulosclerosis without altered survival. In contrast, Os+/− mice on an fvb background (fvb.ROP Os/+) die around 3 months of age of rapidly progressing renal failure. Here we assessed renal function in 4–5 wk old Os/+ and wild type (WT) mice. Kidneys of Os/+ were smaller than WT (135 ± 8 mg vs. 295 ± 20 mg; p<.001) whereas body weight did not differ. GFR determined by FITC-inulin clearance in conscious mice was reduced in Os/+ vs. WT (80 ± 10 vs. 258 ± 21 μl/min, p<.001). Glomerular counts per kidney averaged 1461 ± 163 in Os/+ and 10021 ± 480 in WT (p<.001). Calculated SNGFR was 26 ± 4.6 in Os/+ and 12.6 ± 1.4 nl/min in WT (p=.006), and this correlated with increased stop flow (49.8 ± 1.7 vs. 39.6 ± 1.5 mm Hg; p<0.001) and free flow pressures (17.2 ± 1.1 vs.14.5 ± 0.7 mm Hg, p<0.05). Proximal and distal tubular flow rates were elevated in Os/+ mice while distal Cl concentration was normal. BUN was elevated in Os/+ mice compared to WT (93 ± 8.8 vs. 29 ± 3.5 mg/dl; p<0.01). Ambient urinary osmolarity averaged 748 ± 29 mOsm in Os/+ and 1179 ± 118 mOsm in WT (p=.015). Plasma renin was reduced in Os/+ vs. WT (318 ± 59 vs. 807 ± 86 ng Ang I/ml/hr; p=.001) as was renin mRNA (21 ± 3% of WT normalized by 18s RNA; p<.001). In summary, Os/+ mice have an 85% reduction of nephron number, and this is associated with glomerular hypertension, hyperfiltration and hypertrophy of existing nephrons, likely causes of the progressive deterioration of renal function.