妊娠合并 HELLP 综合征导致孕鼠急性肾损伤，增加 sFlt-1 和 sEng，减少肾脏 T 调节细胞。
Acute kidney injury during pregnancy leads to increased sFlt-1 and sEng and decreased renal T regulatory cells in pregnant rats with HELLP syndrome.
机构信息
Department of Obstetrics & Gynecology, University of Mississippi Medical Center, 2500 North State St, Jackson, MS, 39216, USA.
Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, USA.
出版信息
Biol Sex Differ. 2020 Sep 24;11(1):54. doi: 10.1186/s13293-020-00331-6.
BACKGROUND
The incidence of acute kidney injury (AKI) during pregnancy precedes a high maternal mortality rate of 20-40%. AKI during pregnancy has multiple etiologies; however, the more common are maternal hypertensive disorders, which include preeclampsia and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. Therefore, we sought to assess the impact of AKI on blood pressure, kidney injury, and anti-angiogenic factors during pregnancies with and without HELLP syndrome.
METHODS
On gestational day (GD) 12, mini-osmotic pumps were inserted into a subset of normal pregnant (NP) rats infusing 4.7 μg/kg soluble fms-like tyrosine kinase-1 (sFlt-1) and 7 μg/kg soluble endoglin (sEng) to induce HELLP syndrome. On GD18, the renal pedicles were occluded for 45 min to induce AKI via bilateral ischemia reperfusion in a subset of NP (n = 18) or HELLP (n = 20) rats. Control NP (n = 20) and HELLP (n = 20) rats underwent a SHAM surgery on GD18. Plasma, urine, and maternal organs were saved for further analysis. Renal injury was assessed via renal histopathology, glomerular filtration rate (GFR), T cell infiltration, and assessment of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Data was measured via two-way analysis of variance with Tukey's test for post hoc analysis.
RESULTS
Blood pressures were increased in HELLP+AKI rats (p = 0.0001); both NP+AKI and HELLP+AKI rats had increased lactate dehydrogenase (p < 0.0001) and aspartate aminotransferase levels (p < 0.0001), and decreased platelet levels (p < 0.001) vs. NP rats. HELLP+AKI (p = 0.002) and HELLP rats (p = 0.0002) had evidence of renal fibrosis vs. NP rats. GFR was decreased in HELLP+AKI (p = 0.01) rats vs. NP rats. Urinary KIM-1 was increased in NP+AKI rats vs. NP (p = 0.003) and HELLP rats (p = 0.01). HELLP+AKI rats had increased urinary KIM-1 vs. NP (p = 0.0008) and HELLP rats (p = 0.004) and increased NGAL vs. HELLP rats (p = 0.002). HELLP+AKI rats had increased sFlt-1 (p = 0.009) vs. NP rats. NP+AKI (p = 0.02) and HELLP+AKI (p = 0.007) rats had increased sEng vs. NP rats. CD3CD4 T cells were significantly increased in HELLP+AKI rats vs. NP (p = 0.0002) and NP+AKI (p = 0.05) rats. T regulatory cells were significantly decreased in HELLP+AKI (p = 0.03) and NP+AKI (p = 0.02) rats vs. NP rats; there were no changes between groups in T helper 17 cells (p = 0.34).
CONCLUSION
The findings in this study suggest that AKI during pregnancy contributes to increased blood pressure and biochemical markers for HELLP syndrome, creates an anti-angiogenic imbalance, and exacerbates kidney injury as shown on histopathology, GFR, and kidney injury markers.
背景
妊娠期间急性肾损伤（AKI）的发病率导致母体死亡率高达 20-40%。妊娠期间 AKI 的病因有多种，其中更常见的是母体高血压疾病，包括子痫前期和 HELLP（溶血、肝酶升高、血小板减少）综合征。因此，我们试图评估 AKI 对伴有和不伴有 HELLP 综合征的妊娠期间血压、肾脏损伤和抗血管生成因子的影响。
方法
在妊娠第 12 天，将微型渗透泵插入一小部分正常妊娠（NP）大鼠中，以 4.7μg/kg 的可溶性 fms 样酪氨酸激酶-1（sFlt-1）和 7μg/kg 的可溶性内皮糖蛋白（sEng）诱导 HELLP 综合征。在妊娠第 18 天，通过双侧缺血再灌注对一小部分 NP（n=18）或 HELLP（n=20）大鼠的肾蒂进行 45 分钟的阻断，以诱导 AKI。NP（n=20）和 HELLP（n=20）的对照大鼠在妊娠第 18 天接受 SHAM 手术。保存血浆、尿液和母体器官进行进一步分析。通过肾组织病理学、肾小球滤过率（GFR）、T 细胞浸润以及评估肾损伤分子-1（KIM-1）和中性粒细胞明胶酶相关脂质运载蛋白（NGAL）来评估肾脏损伤。数据通过双因素方差分析进行测量，并采用 Tukey 检验进行事后分析。
结果
HELLP+AKI 大鼠的血压升高（p=0.0001）；NP+AKI 和 HELLP+AKI 大鼠的乳酸脱氢酶（p<0.0001）和天冬氨酸转氨酶水平（p<0.0001）升高，血小板水平（p<0.001）降低，与 NP 大鼠相比。HELLP+AKI（p=0.002）和 HELLP 大鼠（p=0.0002）的肾脏纤维化证据与 NP 大鼠相比。HELLP+AKI 大鼠的 GFR 降低（p=0.01），与 NP 大鼠相比。NP+AKI 大鼠的尿 KIM-1 增加（p=0.003），与 NP 大鼠和 HELLP 大鼠相比。HELLP+AKI 大鼠的尿 KIM-1 高于 NP 大鼠（p=0.0008）和 HELLP 大鼠（p=0.01），高于 HELLP 大鼠（p=0.004），尿 NGAL 增加，与 HELLP 大鼠（p=0.002）相比。HELLP+AKI 大鼠的 sFlt-1 增加（p=0.009），与 NP 大鼠相比。NP+AKI（p=0.02）和 HELLP+AKI（p=0.007）大鼠的 sEng 高于 NP 大鼠。HELLP+AKI 大鼠的 CD3+CD4+T 细胞显著高于 NP 大鼠（p=0.0002）和 NP+AKI 大鼠（p=0.05）。HELLP+AKI 大鼠和 NP+AKI 大鼠的 T 调节细胞显著减少（p=0.03），与 NP 大鼠相比；各组 T 辅助 17 细胞无变化（p=0.34）。
结论
本研究结果表明，妊娠期间 AKI 导致血压升高和 HELLP 综合征的生化标志物增加，造成抗血管生成失衡，并通过组织病理学、GFR 和肾脏损伤标志物加重肾脏损伤。
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