Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Int J Mol Sci. 2023 Mar 30;24(7):6500. doi: 10.3390/ijms24076500.
Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8-10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12-14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 ( = 0.0046, = 0.031, respectively) and renal KIM-1 immunostaining ( = 0.004, = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression ( = 0.012) and cardiac injury/stroke composite score ( = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score ( < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1.
肾损伤分子 1（KIM-1）是肾损伤的生物标志物，也是心血管疾病的预测因子。醛固酮通过激活盐皮质激素受体与心脏和肾脏损伤有关。然而，目前尚不清楚盐皮质激素受体激活和阻断对 KIM-1 的影响。我们研究了 L-NAME/ANG II 诱导的心肾损伤模型中肾脏 KIM-1 是否增加，以及盐皮质激素受体阻断是否可预防 KIM-1 的增加。由于他汀类药物的使用与醛固酮降低有关，我们还研究了给予亲脂性他汀类药物（辛伐他汀）或亲水性他汀类药物（普伐他汀）是否可预防肾脏 KIM-1 的增加。雌性 Wistar 大鼠（8-10 周龄），给予高盐饮食（1.6% Na+），随机分为以下 14 天条件：对照组；L-NAME（0.2 mg/mL 于饮用水中）/ANG II（225 ug/kg/天，第 12-14 天）；L-NAME/ANG II+依普利酮（100 mg/kg/天，po）；L-NAME/ANG II+普伐他汀（20 mg/kg/天，po）；L-NAME/ANG II+辛伐他汀（20 mg/kg/天，po）。与对照组相比，接受 L-NAME/ANG II 治疗的组血压、血浆和尿液醛固酮、心脏损伤/中风复合评分和肾脏 KIM-1 明显更高。依普利酮和辛伐他汀均降低 24 小时尿 KIM-1（ = 0.0046， = 0.031，分别）和肾脏 KIM-1 免疫染色（ = 0.004， = 0.037，分别）。依普利酮还降低了肾脏 KIM-1 mRNA 表达（ = 0.012）和心脏损伤/中风复合评分（ = 0.04）。普伐他汀未影响这些损伤标志物。24 小时尿 KIM-1、肾脏 KIM-1 免疫染色和肾脏 KIM-1 mRNA 表达与心脏损伤/中风复合评分相关（ < 0.0001，Spearman 等级相关=0.69、0.66、0.59，分别）。总之，L-NAME/ANG II 增加肾脏 KIM-1，依普利酮和辛伐他汀均可减轻肾脏 KIM-1 的增加。
Zotero 插件
