Fountoulakis Nikolaos, Psefteli Paraskevi-Maria, Maltese Giuseppe, Gnudi Luigi, Siow Richard C, Karalliedde Janaka
Unit for Metabolic Medicine, School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences and Medicine, King's British Heart Foundation Center of Research Excellence, King's College London, London, UK.
Kidney Int Rep. 2023 Apr 30;8(7):1380-1388. doi: 10.1016/j.ekir.2023.04.021. eCollection 2023 Jul.
Aortic pulse wave velocity (Ao-PWV) predicts cardiovascular and kidney disease in type 2 diabetes (T2D). Klotho is a circulating antiaging hormone (sKlotho) with putative cardiorenal protective effects. The relationship between sKlotho and Ao-PWV in diabetic kidney disease (DKD) is unknown.
In a cross-sectional cohort study, the correlation of sKlotho measured by a validated immunoassay, and Ao-PWV measured by applanation tonometry, was investigated in 172 participants with T2D and early stage DKD (all had estimated glomerular filtration rate [eGFR] >45 ml/min) on stable renin angiotensin system (RAS) inhibition. In cultured human aortic smooth muscle cells (HASMCs) stimulated with angiotensin II (AngII), the effects of recombinant human sKlotho pretreatment were assessed on intracellular calcium ([Ca]) responses and expression of proteins associated with proosteogenic HASMC phenotypes.
Mean (range) age of the cohort was 61.3 years (40-82) and 65% were male. Mean (±SD) Ao-PWV was 11.4 (±2.3) m/s, eGFR 78.8 (±23.5) and median (interquartile range) sKlotho of 358.5 (194.2-706.3) pg/ml. In multivariable linear regression analyses, we observed a statistically significant inverse relationship between sKlotho and Ao-PWV, which was independent of clinical risk factors for cardiorenal disease. Pretreatment of cultured HASMC with sKlotho significantly attenuated AngII-stimulated [Ca] transients and reduced osteogenic collagen (Col1a2) expression.
In individuals with T2D and early DKD, lower levels of sKlotho are associated with increased Ao-PWV. Taken together with the direct effect of sKlotho on mediators of aortic wall stiffness , these findings may explain the enhanced risk of cardiorenal disease in DKD.
主动脉脉搏波速度（Ao-PWV）可预测2型糖尿病（T2D）患者的心血管疾病和肾脏疾病。α-klotho是一种具有循环抗老化作用的激素（可溶性α-klotho，sKlotho），可能具有心脏和肾脏保护作用。sKlotho与糖尿病肾病（DKD）患者的Ao-PWV之间的关系尚不清楚。
在一项横断面队列研究中，我们对172例接受稳定肾素-血管紧张素系统（RAS）抑制治疗的T2D和早期DKD患者（估算肾小球滤过率[eGFR]均>45 ml/min）进行了研究，通过经过验证的免疫分析法测定sKlotho，并采用压平式眼压计测量Ao-PWV，分析两者之间的相关性。在用血管紧张素II（AngII）刺激的人主动脉平滑肌细胞（HASMCs）培养物中，评估重组人sKlotho预处理对细胞内钙（[Ca]）反应以及与促骨生成HASMC表型相关蛋白表达的影响。
该队列的平均（范围）年龄为61.3岁（40 - 82岁），男性占65%。平均（±标准差）Ao-PWV为11.4（±2.3）m/s，eGFR为78.8（±23.5），sKlotho中位数（四分位间距）为358.5（194.2 - 706.3）pg/ml。在多变量线性回归分析中，我们观察到sKlotho与Ao-PWV之间存在统计学上显著的负相关关系，且独立于心脏和肾脏疾病的临床风险因素。用sKlotho对培养的HASMC进行预处理可显著减弱AngII刺激引起的[Ca]瞬变，并降低成骨胶原蛋白（Col1a2）的表达。
在T2D和早期DKD患者中，较低水平的sKlotho与较高的Ao-PWV相关。结合sKlotho对主动脉壁硬度介质的直接作用，这些发现可能解释了DKD患者心脏和肾脏疾病风险增加的原因。
