Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Am J Physiol Renal Physiol. 2011 Feb;300(2):F330-8. doi: 10.1152/ajprenal.00261.2010. Epub 2010 Nov 3.
The present study examined the effect of transfer of portions of chromosome 1 that includes (FHH.1(BN) AR(+) strain) or excludes (control FHH.1(BN) AR(-) strain) a 4.3-Mb region from the Brown Norway (BN) rat that restores the autoregulation (AR) of renal blood flow (RBF) on the development of hypertension and renal injury in congenic strains of Fawn Hooded Hypertensive (FHH) rats. FHH and control AR(-) rats exhibited poor autoregulation of RBF, and glomerular capillary pressure (Pgc) rose by 19 ± 2 mmHg in FHH rats when renal perfusion pressure (RPP) was increased from 100 to 150 mmHg. In contrast, RBF was well autoregulated in the AR(+) strain, and Pgc only increased by 3 ± 1 mmHg when RPP was increased over this range. Baseline mean arterial pressure (MAP) at 12 wk of age was similar in all strains and averaged 122 mmHg. MAP increased significantly in FHH rats and was significantly higher by 12 mmHg in 21-wk-old FHH rats than in the FHH.1(BN) congenic strains. Protein excretion rose from 5 ± 1 to 397 ± 29 mg/day in 6- vs. 21-wk-old FHH rats. In contrast, protein excretion only increased to 139 ± 21 mg/day in the control AR(-) strain, and it did not increase significantly in the AR(+) strain. Glomerular permeability to albumin was similar in all strains at 6 wk of age. It increased significantly in 9-wk-old FHH and control AR(-) rats, but not in the AR(+) strain. The levels of matrix metalloproteinase (MMP)-2 and transforming growth factor (TGF)-β2 protein were significantly higher in the renal cortex of 9-wk-old FHH rats compared with the levels seen in the AR(+) strain. These data indicate that transfer of a 4.3-Mb region of BN chromosome 1 into the FHH genetic background improves autoregulation of RBF, normalizes Pgc, and slows the progression of renal disease.
本研究探讨了将包含（FHH.1(BN) AR(+) 株）或不包含（对照 FHH.1(BN) AR(-) 株）来自 Brown Norway（BN）大鼠的 4.3-Mb 区域的部分染色体 1 转移到 Fawn Hooded 高血压（FHH）大鼠的同源系中对高血压和肾损伤发展的影响。FHH 和对照 AR(-) 大鼠的肾血流自动调节（AR）不良，当肾灌注压（RPP）从 100 增加到 150mmHg 时，FHH 大鼠的肾小球毛细血管压（Pgc）升高 19 ± 2mmHg。相比之下，AR(+) 株的 RBF 自动调节良好，当 RPP 在该范围内增加时，Pgc 仅增加 3 ± 1mmHg。12 周龄时所有品系的基础平均动脉压（MAP）相似，平均为 122mmHg。MAP 在 FHH 大鼠中显著升高，21 周龄 FHH 大鼠比 FHH.1(BN) 同系大鼠高 12mmHg。6 周龄时，FHH 大鼠的蛋白排泄从 5 ± 1 增加到 397 ± 29mg/天。相比之下，对照 AR(-) 株的蛋白排泄仅增加到 139 ± 21mg/天，而在 AR(+) 株中没有显著增加。6 周龄时所有品系的肾小球对白蛋白的通透性相似。在 9 周龄的 FHH 和对照 AR(-) 大鼠中显著增加，但在 AR(+) 株中没有增加。9 周龄 FHH 大鼠肾皮质中基质金属蛋白酶（MMP）-2 和转化生长因子（TGF）-β2 蛋白的水平明显高于 AR(+) 株。这些数据表明，将 BN 染色体 1 的 4.3-Mb 区域转移到 FHH 遗传背景中可改善 RBF 的自动调节，使 Pgc 正常化，并减缓肾脏疾病的进展。
