Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
J Pharmacol Exp Ther. 2021 Feb;376(2):240-249. doi: 10.1124/jpet.120.000353. Epub 2020 Dec 4.
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that has been implicated in the pathophysiology of kidney disease. However, few studies have attempted to measure changes in the levels of various LPA species in the kidney after the development of renal disease. The present study measured the renal LPA levels during the development of kidney disease in rat models of hypertension, diabetes, and obstructive nephropathy using liquid chromatography/mass spectrometry/mass spectrometry. LPA levels (sum of 16:0, 18:0, 18:1, 18:2, and 20:4 LPA) were higher in the renal cortex of hypertensive Dahl salt-sensitive (Dahl S) rats fed a high-salt diet than those in normotensive rats fed a low-salt diet (296.6 ± 22.9 vs. 196.3 ± 8.5 nmol/g protein). LPA levels were elevated in the outer medulla of the kidney of streptozotocin-induced type 1 diabetic Dahl S rats compared with control rats (624.6 ± 129.5 vs. 318.8 ± 17.1 nmol/g protein). LPA levels were also higher in the renal cortex of 18-month-old, type 2 diabetic nephropathy (T2DN) rats with more severe renal injury than in 6-month-old T2DN rats (184.9 ± 20.9 vs. 116.9 ± 6.0 nmol/g protein). LPA levels also paralleled the progression of renal fibrosis in the renal cortex of Sprague-Dawley rats after unilateral ureteral obstruction (UUO). Administration of an LPA receptor antagonist, Ki16425, reduced the degree of renal fibrosis in UUO rats. These results suggest that the production of renal LPA increases during the development of renal injury and contributes to renal fibrosis. SIGNIFICANCE STATEMENT: The present study reveals that the lysophosphatidic acid (LPA) levels increase in the kidney in rat models of hypertension, diabetes, and obstructive nephropathy, and administration of an LPA receptor antagonist attenuates renal fibrosis. Therapeutic approaches that target the formation or actions of renal LPA might be renoprotective and have therapeutic potential.
溶血磷脂酸（LPA）是一种生物活性脂质介质，与肾脏疾病的病理生理学有关。然而，很少有研究试图测量在肾脏疾病发生后，各种 LPA 物种在肾脏中的水平变化。本研究使用液相色谱/质谱/质谱法测量了高血压、糖尿病和梗阻性肾病大鼠模型在肾脏疾病发展过程中的肾脏 LPA 水平。在高盐饮食喂养的高血压达尔斯盐敏感（Dahl S）大鼠的肾脏皮质中，LPA 水平（16:0、18:0、18:1、18:2 和 20:4 LPA 的总和）高于低盐饮食喂养的正常血压大鼠（296.6 ± 22.9 与 196.3 ± 8.5 nmol/g 蛋白）。与对照组相比，链脲佐菌素诱导的 1 型糖尿病达尔斯 S 大鼠的肾脏外髓质中 LPA 水平升高（624.6 ± 129.5 与 318.8 ± 17.1 nmol/g 蛋白）。与 6 月龄 T2DN 大鼠相比，18 月龄、2 型糖尿病肾病（T2DN）大鼠的肾脏皮质中 LPA 水平也更高，且肾脏损伤更严重（184.9 ± 20.9 与 116.9 ± 6.0 nmol/g 蛋白）。LPA 水平也与单侧输尿管梗阻（UUO）后 Sprague-Dawley 大鼠肾脏皮质中肾纤维化的进展平行。给予 LPA 受体拮抗剂 Ki16425 可减少 UUO 大鼠的肾纤维化程度。这些结果表明，在肾脏损伤的发展过程中，肾脏中 LPA 的产生增加，并有助于肾纤维化。意义：本研究表明，在高血压、糖尿病和梗阻性肾病大鼠模型中，LPA 水平在肾脏中升高，给予 LPA 受体拮抗剂可减轻肾纤维化。针对肾脏 LPA 形成或作用的治疗方法可能具有肾保护作用并具有治疗潜力。
