Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany.
Institute of Pharmacology and Toxicology, Johann Wolfgang Goethe-University, Frankfurt, Germany.
Kidney Int. 2017 Apr;91(4):818-829. doi: 10.1016/j.kint.2016.11.003. Epub 2016 Dec 28.
Deletion of cyclooxygenase-2 (COX-2) causes impairment of postnatal kidney development. Here we tested whether the renin angiotensin system contributes to COX-2-dependent nephrogenesis in mice after birth and whether a rescue of impaired renal development and function in COX-2 mice was achievable. Plasma renin concentration in mouse pups showed a birth peak and a second peak around day P8 during the first 10 days post birth. Administration of the angiotensin II receptor AT1 antagonist telmisartan from day P1 to P3 did not result in cortical damage. However, telmisartan treatment from day P3 to P8, the critical time frame of renal COX-2 expression, led to hypoplastic glomeruli, a thinned subcapsular cortex and maturational arrest of superficial glomeruli quite similar to that observed in COX-2 mice. In contrast, AT2 receptor antagonist PD123319 was without any effect on renal development. Inhibition of the renin angiotensin system by aliskiren and enalapril caused similar glomerular defects as telmisartan. Administration of the AT1 receptor agonist L162313 to COX-2 pups improved kidney growth, ameliorated renal defects, but had no beneficial effect on reduced cortical mass. L162313 rescued impaired renal function by reducing serum urea and creatinine and mitigated pathologic albumin excretion. Moreover, glomerulosclerosis in the kidneys of COX-2 mice was reduced. Thus, angiotensin II-AT1-receptor signaling is necessary for COX-2-dependent normal postnatal nephrogenesis and maturation.
环氧化酶-2（COX-2）的缺失会导致出生后肾脏发育受损。在这里，我们测试了肾素-血管紧张素系统（renin angiotensin system）是否有助于出生后小鼠中 COX-2 依赖性肾发生，以及 COX-2 小鼠的肾脏发育和功能损伤是否可以得到挽救。出生后第 10 天内，幼鼠的血浆肾素浓度出现出生高峰和第 8 天左右的第二个高峰。从出生后第 1 天至第 3 天给予血管紧张素 II 受体 AT1 拮抗剂替米沙坦治疗不会导致皮质损伤。然而，从第 3 天至第 8 天，即肾脏 COX-2 表达的关键时间框架内，替米沙坦治疗会导致肾小球发育不全、皮质下区域变薄以及浅层肾小球成熟停滞，这与 COX-2 小鼠中观察到的情况非常相似。相比之下，AT2 受体拮抗剂 PD123319 对肾脏发育没有任何影响。肾素-血管紧张素系统的抑制通过阿利克仑和依那普利引起类似的肾小球缺陷。AT1 受体激动剂 L162313 给予 COX-2 幼鼠可改善肾脏生长，改善肾脏缺陷，但对减少的皮质质量没有有益影响。L162313 通过降低血清尿素和肌酐来改善受损的肾功能，并减轻病理性白蛋白排泄。此外，COX-2 小鼠肾脏中的肾小球硬化减少。因此，血管紧张素 II-AT1 受体信号传导对于 COX-2 依赖性正常出生后肾发生和成熟是必要的。
