Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Matrix Biol. 2011 Jan;30(1):62-9. doi: 10.1016/j.matbio.2010.09.006. Epub 2010 Oct 7.
A functional renin-angiotensin system (RAS) is required for normal kidney development. Neonatal inhibition of the RAS in rats results in long-term pathological renal phenotype and causes hyaluronan (HA), which is involved in morphogenesis and inflammation, to accumulate. To elucidate the mechanisms, intrarenal HA content was followed during neonatal completion of nephrogenesis with or without angiotensin converting enzyme inhibition (ACEI) together with mRNA expression of hyaluronan synthases (HAS), hyaluronidases (Hyal), urinary hyaluronidase activity and cortical lymphatic vessels, which facilitate the drainage of HA from the tissue. In 6-8days old control rats cortical HA content was high and reduced by 93% on days 10-21, reaching adult low levels. Medullary HA content was high on days 6-8 and then reduced by 85% to 12-fold above cortical levels at day 21. In neonatally ACEI-treated rats the reduction in HA was abolished. Temporal expression of HAS2 corresponded with the reduction in HA content in the normal kidney. In ACEI-treated animals cortical HAS2 remained twice the expression of controls. Medullary Hyal1 increased in controls but decreased in ACEI-treated animals. Urine hyaluronidase activity decreased with time in control animals while in ACEI-treated animals it was initially 50% lower and did not change over time. Cells expressing the lymphatic endothelial mucoprotein podoplanin in ACEI-treated animals were increased 18-fold compared to controls suggesting compensation. In conclusion, the high renal HA content is rapidly reduced due to reduced HAS2 and increased Hyal1 mRNA expressions. Normal angiotensin II function is crucial for inducing these changes. Due to the extreme water-attracting and pro-inflammatory properties of HA, accumulation in the neonatally ACEI-treated kidneys may partly explain the pathological renal phenotype of the adult kidney, which include reduced urinary concentration ability and tubulointerstitial inflammation.
正常的肾脏发育需要功能性肾素-血管紧张素系统（RAS）。在新生大鼠中抑制 RAS 会导致长期的病理性肾脏表型，并导致参与形态发生和炎症的透明质酸（HA）积累。为了阐明这些机制，我们在新生大鼠完成肾发生的过程中，同时观察或不观察血管紧张素转换酶抑制剂（ACEI）抑制的情况下，观察肾内 HA 含量，并检测透明质酸合酶（HAS）、透明质酸酶（Hyal）的 mRNA 表达、尿透明质酸酶活性和皮质淋巴管，这些都有助于 HA 从组织中排出。在 6-8 天大的对照组大鼠中，皮质 HA 含量较高，在第 10-21 天减少了 93%，达到成年时的低水平。髓质 HA 含量在第 6-8 天较高，然后减少 85%，在第 21 天达到皮质水平的 12 倍以上。在新生期接受 ACEI 治疗的大鼠中，HA 的减少被消除。HAS2 的时间表达与正常肾脏中 HA 含量的减少相对应。在 ACEI 治疗的动物中，皮质 HAS2 的表达仍然是对照组的两倍。髓质 Hyal1 在对照组中增加，但在 ACEI 治疗的动物中减少。对照组中尿透明质酸酶活性随时间减少，而 ACEI 治疗的动物中，初始活性降低 50%，且随时间变化不变。在 ACEI 治疗的动物中，表达淋巴管内皮黏蛋白 podoplanin 的细胞增加了 18 倍，这表明存在代偿。总之，由于 HAS2 减少和 Hyal1 mRNA 表达增加，肾脏中的高 HA 含量迅速减少。正常的血管紧张素 II 功能对于诱导这些变化至关重要。由于 HA 具有极强的吸水和促炎特性，在新生期接受 ACEI 治疗的肾脏中积累可能部分解释了成年肾脏的病理性肾脏表型，包括降低的尿浓缩能力和肾小管间质炎症。
