Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid-Mediated Kidney Injury in Diabetic Nephropathy
Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid-Mediated Kidney Injury in Diabetic Nephropathy
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DOI：
10.1681/asn.2013090980
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发表时间：
2015-03-01
影响因子：
13.6
通讯作者：
Pozzi, Ambra
中科院分区：
文献类型：
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作者：
Gangadhariah, Mahesha H.;Luther, James M.;Pozzi, Ambra
在肾脏中，20-羟基二十碳四烯酸（20-HETE）是一种主要的细胞色素P4504（Cyp 4）衍生的类二十烷酸，其增强肾血管的血管收缩并诱导高血压、肾小管细胞肥大和足细胞凋亡。高血压和足细胞损伤导致糖尿病肾病，是疾病进展的强有力预测因素。在这项研究中，我们确定了20-HETE影响糖尿病肾病进展的机制。我们使用Cyp 4a 14 KO雄性小鼠，其由于Cyp 4a 12介导的20-HETE产生增加而表现出雄激素敏感性高血压。我们发现，通过注射链脲佐菌素诱导1型糖尿病后，Cyp 4a 14 KO雄性小鼠比链脲佐菌素治疗的野生型小鼠发生更严重的肾脏疾病，其特征为白蛋白尿增加，系膜扩张，肾小球基质沉积和肾小球基底膜厚度。去势减弱雄激素介导的Cyp 4a 12合成和20-HETE产生，使血压正常化，并改善糖尿病Cyp 4a 14 KO小鼠的肾损伤。值得注意的是，用20-HETE拮抗剂或使BP正常化而不影响Cyp 4a 12表达和20-HETE生物合成的药物治疗也改善Cyp 4a 14 KO雄性小鼠中糖尿病介导的肾损伤和白蛋白尿。总之，这些结果表明，高血压是20-HETE驱动的糖尿病介导的肾损伤的主要贡献者。
In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P4504 (Cyp4) derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetes-mediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE-driven diabetes-mediated kidney injury.