Wheelock Kevin M, Cai Jian, Looker Helen C, Merchant Michael L, Nelson Robert G, Fufaa Gudeta D, Weil E Jennifer, Feldman Harold I, Vasan Ramachandran S, Kimmel Paul L, Rovin Brad H, Mauer Michael, Klein Jon B
National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States of America.
University of Louisville, Louisville, Kentucky, United States of America.
PLoS One. 2017 Jul 10;12(7):e0180964. doi: 10.1371/journal.pone.0180964. eCollection 2017.
To examine the association of bradykinin and related peptides with the development of diabetic nephropathy lesions in 243 participants with type 1 diabetes (T1D) from the Renin-Angiotensin System Study who, at baseline, were normoalbuminuric, normotensive and had normal or increased glomerular filtration rate (GFR).
Plasma concentrations of bradykinin and related peptides were measured at baseline by quantitative mass spectrometry. All participants were randomly assigned at baseline to receive placebo, enalapril or losartan during the 5 years between kidney biopsies. Kidney morphometric data were available from kidney biopsies at baseline and after 5 years. Relationships of peptides with changes in morphometric variables were assessed using multiple linear regression after adjustment for age, sex, diabetes duration, HbA1c, mean arterial pressure, treatment assignment and, for longitudinal analyses, baseline structure.
Baseline median albumin excretion rate of study participants was 5.0 μg/min, and mean GFR was 128 mL/min/1.73 m2. After multivariable adjustment, higher plasma concentration of bradykinin (1-8) was associated with greater glomerular volume (partial r = 0.191, P = 0.019) and total filtration surface area (partial r = 0.211, P = 0.010), and higher bradykinin (1-7) and hyp3-bradykinin (1-7) were associated with lower cortical interstitial fractional volume (partial r = -0.189, P = 0.011; partial r = -0.164, P = 0.027 respectively). In longitudinal analyses, higher bradykinin was associated with preservation of surface density of the peripheral glomerular basement membrane (partial r = 0.162, P = 0.013), and for participants randomized to losartan, higher hyp3-bradykinin (1-8) was associated with more limited increase in cortical interstitial fractional volume (partial r = -0.291, P = 0.033).
Higher plasma bradykinin and related peptide concentrations measured before clinical onset of diabetic nephropathy in persons with T1D were associated with preservation of glomerular structures, suggesting that elevations of these kinin concentrations may reflect adaptive responses to early renal structural changes in diabetic nephropathy.
在肾素 - 血管紧张素系统研究的243名1型糖尿病（T1D）参与者中，研究缓激肽及相关肽与糖尿病肾病病变发展的关联。这些参与者在基线时尿白蛋白正常、血压正常，肾小球滤过率（GFR）正常或升高。
通过定量质谱法在基线时测量血浆缓激肽及相关肽的浓度。所有参与者在基线时被随机分配，在两次肾活检之间的5年期间接受安慰剂、依那普利或氯沙坦治疗。可获得基线时和5年后肾活检的肾脏形态学数据。在调整年龄、性别、糖尿病病程、糖化血红蛋白、平均动脉压、治疗分配以及纵向分析中的基线结构后，使用多元线性回归评估肽与形态学变量变化的关系。
研究参与者的基线尿白蛋白排泄率中位数为5.0μg/分钟，平均GFR为128mL/分钟/1.73m²。经过多变量调整后，较高的血浆缓激肽（1 - 8）浓度与更大的肾小球体积（偏相关系数r = 0.191，P = 0.019）和总滤过表面积（偏相关系数r = 0.211，P = 0.010）相关，较高的缓激肽（1 - 7）和hyp3 - 缓激肽（1 - 7）与较低的皮质间质分数体积相关（偏相关系数分别为r = -0.189，P = 0.011；r = -0.164，P = 0.027）。在纵向分析中，较高的缓激肽与外周肾小球基底膜表面密度保存相关（偏相关系数r = 0.162，P = 0.013），对于随机分配接受氯沙坦治疗的参与者，较高的hyp3 - 缓激肽（1 - 8）与皮质间质分数体积增加更有限相关（偏相关系数r = -0.291，P = 0.033）。
在T1D患者糖尿病肾病临床发病前测量的较高血浆缓激肽及相关肽浓度与肾小球结构保存相关，表明这些激肽浓度升高可能反映了对糖尿病肾病早期肾脏结构变化的适应性反应。
