McPherson Elizabeth A, Luo Zaiming, Brown Rachel A, LeBard Linda S, Corless Christopher C, Speth Robert C, Bagby Susan P
Department of Medicine and Pathology, Oregon Health and Science University and Portland, VA Medical Center, Portland, Oregon 97239, USA.
J Am Soc Nephrol. 2004 Feb;15(2):493-500. doi: 10.1097/01.asn.0000109782.28991.26.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by exuberant inflammation and fibrosis, a process believed to contribute to progressive loss of normal renal function. Despite early-onset hypertension and intrarenal renin/angiotensin II (AngII) activation, angiotensin-converting enzyme (ACE) inhibition does not consistently confer renal protection in ADPKD. The hypothesis was that mast cells within the inflammatory interstitium release chymase, an enzyme capable of efficient conversion of AngI to AngII, providing an ACE-independent route of AngII generation. End-stage ADPKD renal tissue extracts and cyst fluids were assayed for time-dependent, chymostatin-inhibitable conversion of (125)I-AngI to (125)I-AngII under conditions of ACE and aminopeptidase inhibition by means of HPLC. Thirteen of 14 ADPKD kidney extracts exhibited chymase-like AngII-generating capacity; calculated initial reaction rates averaged 3.9 +/- 2.9 fmol AngII/min/ micro g protein with a mean maximal conversion of 55% +/- 30% of added substrate. AngII-generating activity was both protein and substrate dependent. All five cyst fluid samples were negative. Chymase-like activity was detectable in only three of six non-ADPKD kidney extracts. Immunoreactive chymase protein was present in/around mast cells within the fibrotic renal interstitium in all samples. Findings demonstrate for the first time the presence of mast cells, mast cell-associated immunoreactive chymase protein, and chymase-like AngII generating capacity in ADPKD cystic kidneys. Results support the potential for ACE-independent AngII generation and for mast cell-initiated inflammatory processes in ADPKD, each with therapeutic implications for ADPKD renal progression.
常染色体显性遗传性多囊肾病（ADPKD）的特征是炎症和纤维化过度，这一过程被认为会导致正常肾功能的逐渐丧失。尽管存在早发性高血压和肾内肾素/血管紧张素II（AngII）激活，但血管紧张素转换酶（ACE）抑制在ADPKD中并不能始终提供肾脏保护作用。研究假设是，炎症间质中的肥大细胞释放糜酶，这是一种能够将AngI高效转化为AngII的酶，提供了一条不依赖ACE的AngII生成途径。通过高效液相色谱法，在ACE和氨肽酶抑制的条件下，对终末期ADPKD肾组织提取物和囊液进行检测，以确定（125）I-AngI向（125）I-AngII的时间依赖性、抑肽酶抑制性转化。14份ADPKD肾提取物中有13份表现出类似糜酶的AngII生成能力；计算得出的初始反应速率平均为3.9±2.9 fmol AngII/分钟/微克蛋白质，平均最大转化率为添加底物的55%±30%。AngII生成活性既依赖于蛋白质也依赖于底物。所有5份囊液样本均为阴性。在6份非ADPKD肾提取物中，只有3份检测到类似糜酶的活性。在所有样本中，纤维化肾间质内/周围的肥大细胞中存在免疫反应性糜酶蛋白。研究结果首次证明了ADPKD囊性肾中存在肥大细胞、与肥大细胞相关的免疫反应性糜酶蛋白以及类似糜酶的AngII生成能力。结果支持了在ADPKD中存在不依赖ACE的AngII生成以及肥大细胞引发的炎症过程的可能性，这两者对ADPKD肾脏进展均具有治疗意义。
