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Acute kidney injury during pregnancy leads to increased sFlt-1 and sEng and decreased renal T regulatory cells in pregnant rats with HELLP syndrome
Biology of Sex Differences ( IF 4.9 ) Pub Date : 2020-09-24 , DOI: 10.1186/s13293-020-00331-6
Jamie Szczepanski 1 , Shauna-Kay Spencer 1 , Ashley Griffin 2 , Teylor Bowles 1 , Jan Michael Williams 3 , Patrick B Kyle 4 , John Polk Dumas 1 , Sarah Araji 1 , Kedra Wallace 1
Affiliation  

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. 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. 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. CD3+CD4+ 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). 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.

中文翻译:


妊娠期急性肾损伤导致 HELLP 综合征妊娠大鼠 sFlt-1 和 sEng 增加,肾 T 调节细胞减少



妊娠期间急性肾损伤 (AKI) 的发生率高达 20-40%。妊娠期 AKI 有多种病因;然而,更常见的是孕产妇高血压疾病,包括先兆子痫和 HELLP(溶血、肝酶升高、血小板低)综合征。因此,我们试图评估 AKI 对患有和不患有 HELLP 综合征的妊娠期间血压、肾损伤和抗血管生成因子的影响。在妊娠第 12 天 (GD),将微型渗透泵插入一组正常妊娠 (NP) 大鼠体内,注入 4.7 μg/kg 可溶性 fms 样酪氨酸激酶-1 (sFlt-1) 和 7 μg/kg 可溶性内皮因子 (endoglin)。 sEng)诱发 HELLP 综合征。在 GD18 上,肾蒂被闭塞 45 分钟,通过对 NP (n = 18) 或 HELLP (n = 20) 大鼠子集进行双侧缺血再灌注诱导 AKI。对照 NP (n = 20) 和 HELLP (n = 20) 大鼠在 GD18 上接受 SHAM 手术。保存血浆、尿液和母体器官以供进一步分析。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) 的评估来评估肾损伤。数据通过双向方差分析和图基事后分析检验进行测量。 HELLP+AKI 大鼠的血压升高 (p = 0.0001);与 NP 大鼠相比,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) 均升高,血小板水平降低 (p < 0.001)。与 NP 大鼠相比,HELLP+AKI (p = 0.002) 和 HELLP 大鼠 (p = 0.0002) 有肾纤维化的证据。与 NP 大鼠相比,HELLP+AKI (p = 0.01) 大鼠的 GFR 降低。与 NP 大鼠相比,NP+AKI 大鼠的尿液 KIM-1 增加(p = 0。003)和 HELLP 大鼠(p = 0.01)。与 NP (p = 0.0008) 和 HELLP 大鼠 (p = 0.004) 相比,HELLP+AKI 大鼠尿 KIM-1 增加,与 HELLP 大鼠 (p = 0.002) 相比,NGAL 增加。与 NP 大鼠相比,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 有所增加。与 NP (p = 0.0002) 和 NP+AKI (p = 0.05) 大鼠相比,HELLP+AKI 大鼠的 CD3+CD4+ T 细胞显着增加。与 NP 大鼠相比,HELLP+AKI (p = 0.03) 和 NP+AKI (p = 0.02) 大鼠的 T 调节细胞显着减少;辅助 T 细胞 17 组之间没有变化 (p = 0.34)。这项研究的结果表明,妊娠期间的 AKI 会导致 HELLP 综合征的血压和生化标志物升高,产生抗血管生成失衡,并加剧肾损伤(如组织病理学、GFR 和肾损伤标志物所示)。
更新日期:2020-09-24
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