Junho Carolina Victoria Cruz, González-Lafuente Laura, Neres-Santos Raquel Silva, Navarro-García José Alberto, Rodríguez-Sánchez Elena, Ruiz-Hurtado Gema, Carneiro-Ramos Marcela Sorelli
Center of Natural and Human Sciences (CCNH), Federal University of ABC, Santo André, São Paulo, Brazil; Cardiorenal Translational Laboratory, Institute of Research Imas12, Hospital Universitario 12 de Octubre, Madrid, Spain.
Cardiorenal Translational Laboratory, Institute of Research Imas12, Hospital Universitario 12 de Octubre, Madrid, Spain.
Biomed Pharmacother. 2022 Sep;153:113515. doi: 10.1016/j.biopha.2022.113515. Epub 2022 Aug 9.
Renal ischemia and reperfusion injury (IRI) is the main cause of acute kidney injury (AKI). AKI induces the development of cardiac hypertrophy (CH) during cardiorenal syndrome (CRS), and cardiomyocyte calcium mishandling though systemic inflammation after 8 days of renal IRI. Klotho has recently been described as an anti-inflammatory component. Given this, Klotho treatment could prevent or attenuate the inflammation, thereby also preventing electrical cardiac outcomes incurred by CRS. The aim of this study was to investigate the therapeutic role of Klotho in CRS after unilateral renal IRI through its anti-inflammatory action.
We examined renal tissue structure and function, intracellular Ca dynamics in adult ventricular cardiomyocytes and serum cytokine levels from C57BL/6 mice that suffered unilateral renal IRI by occluding the left pedicle for 60 min and reperfusion for 8 days. The animals were treated with recombinant Klotho protein starting from the day of the surgery, then daily for 8 days.
After Klotho treatment for 8 days, the left renal tissue remained damaged, however the renal function was restored due to the right kidney tissue preservation. In parallel, Klotho also prevented an increase in serum interleukin (IL-) 6, IL-1β, and tumor necrosis factor alpha (TNF-α) levels. CH and low cell contraction were also prevented, as well as a decrease in systolic Ca transients and sarco/endoplasmic reticulum Ca-ATPase (SERCA2a) activity measured as Ca transient decay, an increase in spontaneous Ca release and the incidence of pro-arrhythmic events.
The Klotho treatment showed promise, playing an important role in the pathophysiology of CRS. We were unable to observe a total renoprotective role of the compound in the model; in turn, a cardioprotective role of Klotho was demonstrated through the prevention of hypertrophy and normalization of the Ca cycle dysfunction of cardiomyocytes. We propose that Klotho acts in the cardiorenal syndrome by systematically preventing inflammation and increased FGF23, alleviating cardiac outcomes.
肾缺血再灌注损伤（IRI）是急性肾损伤（AKI）的主要原因。AKI在心肾综合征（CRS）期间诱发心脏肥大（CH）的发展，并且在肾IRI 8天后通过全身炎症导致心肌细胞钙处理不当。最近，klotho被描述为一种抗炎成分。鉴于此，klotho治疗可以预防或减轻炎症，从而也预防CRS引起的心脏电活动异常。本研究的目的是通过其抗炎作用研究klotho在单侧肾IRI后CRS中的治疗作用。
我们检查了通过结扎左肾蒂60分钟并再灌注8天而遭受单侧肾IRI的C57BL/6小鼠的肾组织结构和功能、成年心室心肌细胞内的钙动力学以及血清细胞因子水平。从手术当天开始用重组klotho蛋白治疗动物，然后每天治疗8天。
klotho治疗8天后，左肾组织仍然受损，但由于右肾组织的保存，肾功能得以恢复。同时，klotho还可防止血清白细胞介素（IL-）6、IL-1β和肿瘤坏死因子α（TNF-α）水平升高。还可预防CH和低细胞收缩，以及收缩期钙瞬变减少和肌浆网/内质网钙-ATP酶（SERCA2a）活性降低（以钙瞬变衰减衡量）、自发性钙释放增加和心律失常事件发生率增加。
klotho治疗显示出前景，在CRS的病理生理学中起重要作用。我们在该模型中未能观察到该化合物的完全肾脏保护作用；相反，通过预防肥大和使心肌细胞钙循环功能障碍正常化，证明了klotho的心脏保护作用。我们提出，klotho通过系统性地预防炎症和增加成纤维细胞生长因子23（FGF23）来作用于心肾综合征，减轻心脏异常。
