Wang Xuexiang, Johnson Ashley C, Sasser Jennifer M, Williams Jan M, Solberg Woods Leah C, Garrett Michael R
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi;
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Am J Physiol Renal Physiol. 2016 May 1;310(10):F1054-64. doi: 10.1152/ajprenal.00555.2015. Epub 2016 Mar 2.
There is little clinical data of how hypertension may influence individuals with nephron deficiency in the context of being born with a single kidney. We recently developed a new rat model (the heterogeneous stock-derived model of unilateral renal agenesis rat) that is born with a single kidney and exhibits progressive kidney injury and decline in kidney function with age. We hypothesized that DOCA-salt would induce a greater increase in blood pressure and therefore accelerate the progression of kidney injury in rats born with a solitary kidney compared with rats that have undergone unilateral nephrectomy. Time course evaluation of blood pressure, kidney injury, and renal hemodynamics was performed in the following six groups of animals from weeks 13 to 18: 1) DOCA-treated rats with a solitary kidney (DOCA+S group), 2) placebo-treated rats with a solitary kidney, 3) DOCA-treated control rats with two kidneys (DOCA+C group), 4) placebo-treated control rats with two kidneys, 5) DOCA-treated rats with two kidneys that underwent uninephrectomy (DOCA+UNX8 group), and 6) placebo-treated rats with two kidneys that underwent uninephrectomy. DOCA+S rats demonstrated a significant rise (P < 0.05) in blood pressure (192 ± 4 mmHg), proteinuria (205 ± 31 mg/24 h), and a decline in glomerular filtration rate (600 ± 42 μl·min(-1)·g kidney weight(-1)) relative to the DOCA+UNX8 (173 ± 3 mmHg, 76 ± 26 mg/24 h, and 963 ± 36 μl·min(-1)·g kidney weight(-1)) and DOCA+C (154 ± 2 mmHg, 7 ± 1 mg/24 h, and 1,484 ± 121 μl·min(-1)·g kidney weight(-1)) groups. Placebo-treated groups showed no significant change among the three groups. An assessment of renal injury markers via real-time PCR/Western blot analysis and histological analysis was concordant with the measured physiological parameters. In summary, congenital solitary kidney rats are highly susceptible to the induction of hypertension compared with uninephrectomized rats, suggesting that low nephron endowment is an important driver of elevated blood pressure, hastening nephron injury through the transmission of elevated systemic blood pressure and thereby accelerating decline in kidney function.
关于高血压在单肾出生背景下如何影响肾单位缺乏个体的临床数据很少。我们最近开发了一种新的大鼠模型（单侧肾缺如大鼠的异质品系衍生模型），该模型出生时只有一个肾脏，并且随着年龄增长会出现进行性肾损伤和肾功能下降。我们假设，与接受单侧肾切除术的大鼠相比，去氧皮质酮盐会使单肾出生的大鼠血压升高幅度更大，从而加速肾损伤的进展。在第13至18周对以下六组动物进行了血压、肾损伤和肾血流动力学的时间进程评估：1）去氧皮质酮治疗的单肾大鼠（DOCA+S组），2）安慰剂治疗的单肾大鼠，3）去氧皮质酮治疗的双肾对照大鼠（DOCA+C组），4）安慰剂治疗的双肾对照大鼠，5）去氧皮质酮治疗的双肾且接受单侧肾切除术的大鼠（DOCA+UNX8组），6）安慰剂治疗的双肾且接受单侧肾切除术的大鼠。与DOCA+UNX8组（173±3 mmHg、76±26 mg/24 h和963±36 μl·min⁻¹·g肾重⁻¹）和DOCA+C组（154±2 mmHg、7±1 mg/24 h和1484±121 μl·min⁻¹·g肾重⁻¹）相比，DOCA+S大鼠的血压（192±4 mmHg）、蛋白尿（205±31 mg/24 h）显著升高（P<0.05），肾小球滤过率下降（600±42 μl·min⁻¹·g肾重⁻¹）。安慰剂治疗组在三组之间无显著变化。通过实时PCR/蛋白质印迹分析和组织学分析对肾损伤标志物的评估与测量的生理参数一致。总之，与单侧肾切除的大鼠相比，先天性单肾大鼠对高血压的诱导高度敏感，这表明低肾单位禀赋是血压升高的重要驱动因素，通过升高的全身血压传递加速肾单位损伤，从而加速肾功能下降。
