Div. of Nephrology and Hypertension, Dept. of Medicine, The Feinberg School of Medicine, Northwestern Univ., 320 E. Superior, Chicago, IL 60611.
Am J Physiol Renal Physiol. 2013 Aug 15;305(4):F600-11. doi: 10.1152/ajprenal.00600.2012. Epub 2013 Jun 12.
Angiotensin-converting enzyme-2 (ACE2) enhances the degradation of ANG II and its expression is altered in diabetic kidneys, but the regulation of this enzyme in the urine is unknown. Urinary ACE2 was studied in the db/db model of type 2 diabetes and stretozotocin (STZ)-induced type 1 diabetes during several physiological and pharmacological interventions. ACE2 activity in db/db mice was increased in the serum and to a much greater extent in the urine compared with db/m controls. Neither a specific ANG II blocker, telmisartan, nor an ACE inhibitor, captopril, altered the levels of urinary ACE2 in db/db or db/m control mice. High-salt diet (8%) increased whereas low-salt diet (0.1%) decreased urinary ACE2 activity in the urine of db/db mice. In STZ mice, urinary ACE2 was also increased, and insulin decreased it partly but significantly after several weeks of administration. The increase in urinary ACE2 activity in db/db mice reflected an increase in enzymatically active protein with two bands identified of molecular size at 110 and 75 kDa and was associated with an increase in kidney cortex ACE2 protein at 110 kDa but not at 75 kDa. ACE2 activity was increased in isolated tubular preparations but not in glomeruli from db/db mice. Administration of soluble recombinant ACE2 to db/m and db/db mice resulted in a marked increase in serum ACE2 activity, but no gain in ACE2 activity was detectable in the urine, further demonstrating that urinary ACE2 is of kidney origin. Increased urinary ACE2 was associated with more efficient degradation of exogenous ANG II (10(-9) M) in urine from db/db compared with that from db/m mice. Urinary ACE2 could be a potential biomarker of increased metabolism of ANG II in diabetic kidney disease.
血管紧张素转换酶 2（ACE2）增强了 ANG II 的降解，其表达在糖尿病肾脏中发生改变，但尿液中该酶的调节情况尚不清楚。本研究在 2 型糖尿病 db/db 模型和链脲佐菌素（STZ）诱导的 1 型糖尿病中研究了尿液 ACE2，并进行了几种生理和药理学干预。与 db/m 对照相比，db/db 小鼠的血清 ACE2 活性增加，在尿液中的增加幅度更大。特异性 ANG II 阻滞剂替米沙坦或 ACE 抑制剂卡托普利均未改变 db/db 或 db/m 对照小鼠尿液中 ACE2 的水平。高盐饮食（8%）增加，而低盐饮食（0.1%）降低 db/db 小鼠尿液中的 ACE2 活性。在 STZ 小鼠中，尿液 ACE2 也增加，胰岛素在给药数周后部分但显著降低了它。db/db 小鼠尿液中 ACE2 活性的增加反映了酶活性蛋白的增加，有两个大小为 110 和 75 kDa 的条带被鉴定出来，并且与肾皮质 ACE2 蛋白在 110 kDa 处增加但在 75 kDa 处没有增加有关。ACE2 活性在 db/db 小鼠的分离管状制剂中增加，但在肾小球中没有增加。可溶性重组 ACE2 给药至 db/m 和 db/db 小鼠导致血清 ACE2 活性显著增加，但在尿液中未检测到 ACE2 活性的增加，进一步证明尿液 ACE2 来源于肾脏。与 db/m 小鼠相比，db/db 小鼠尿液中存在更多外源性 ANG II（10(-9) M）的有效降解，与 ACE2 活性增加有关。尿液 ACE2 可能是糖尿病肾病中 ANG II 代谢增加的潜在生物标志物。
