Dos Santos Michele Santiago, Canale Daniele, Bernardo Desiree Rita Denelle, Shimizu Maria Heloisa Massola, Seguro Antonio Carlos, Volpini Rildo Aparecido, de Bragança Ana Carolina
Laboratorio de Investigacao Medica 12 (LIM12), Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Laboratorio de Investigacao Medica 12 (LIM12), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Front Med (Lausanne). 2021 Apr 1;8:625647. doi: 10.3389/fmed.2021.625647. eCollection 2021.
Chronic kidney disease (CKD) remains a global public health problem. The initial damage after ischemia/reperfusion (I/R) injury plays an important role in the pathogenesis of acute kidney injury (AKI) and predisposition to CKD. Several studies have been showing that risk factors such as AKI and hypovitaminosis D could also be involved in CKD progression. Vitamin D deficiency (VDD) is associated with hemodynamic changes, activation of inflammatory pathways and renal disease progression (RDP) following I/R-AKI. Strategies for prevention and/or slowing RDP have been determined and the sufficiency of vitamin D has been emerging as a renoprotective factor in many diseases. Therefore, we investigated the effect of the restoration of vitamin D levels in the progression of I/R injury (IRI) in rats previously deficient in vitamin D. On day 30, male Wistar rats were submitted to bilateral 45 min IRI and divided into three groups: IRI, standard diet for 120 days; VDD+IRI, vitamin D-free diet for 120 days; and VDD+IRI+R, vitamin D-free diet in the first 30 days and just after I/R, we reintroduced the standard diet in the last 90 days. After the 120-day protocol, VDD+IRI+R rats presented an improvement in the renal function and renal protein handling followed by a smaller fractional interstitial area. Furthermore, those animals exhibited a reestablishment regarding the hemodynamic parameters and plasma levels of aldosterone, urea and PTH. In addition, the restoration of vitamin D levels reestablished the amount of MCP1 and the renal expressions of CD68+ and CD3+ cells in the VDD+IRI+R rats. Also, VDD+IRI+R rats showed a restoration regarding the amount of collagen type III and renal expressions of fibronectin, vimentin and α-SMA. Such changes were also accompanied by a reestablishment on the renal expression of VDR, Klotho, JG12, and TGF-β1. Our findings indicate that the restoration of vitamin D levels not only improved the renal function and hemodynamics but also reduced the inflammation and fibrosis lesions observed in I/R-AKI associated with VDD. Thus, monitoring of vitamin D status as well as its replacement in the early stages of kidney injury may be a therapeutic alternative in the mitigation of renal disease progression.
慢性肾脏病（CKD）仍是一个全球性的公共卫生问题。缺血/再灌注（I/R）损伤后的初始损害在急性肾损伤（AKI）的发病机制以及CKD的易感性中起重要作用。多项研究表明，诸如AKI和维生素D缺乏等危险因素也可能参与CKD的进展。维生素D缺乏（VDD）与I/R-AKI后的血流动力学变化、炎症途径激活和肾脏疾病进展（RDP）相关。预防和/或减缓RDP的策略已经确定，维生素D的充足性已成为许多疾病中的一种肾脏保护因素。因此，我们研究了恢复先前维生素D缺乏的大鼠维生素D水平对I/R损伤（IRI）进展的影响。在第30天，将雄性Wistar大鼠进行双侧45分钟的IRI，并分为三组：IRI组，给予标准饮食120天；VDD+IRI组，给予不含维生素D的饮食120天；VDD+IRI+R组，在最初30天及I/R后给予不含维生素D的饮食，在最后90天重新引入标准饮食。经过120天的实验方案后，VDD+IRI+R组大鼠的肾功能和肾脏蛋白质处理得到改善，随后肾间质分数面积减小。此外，这些动物在血流动力学参数以及醛固酮、尿素和甲状旁腺激素的血浆水平方面表现出恢复。此外，维生素D水平的恢复使VDD+IRI+R组大鼠的MCP1量以及CD68+和CD3+细胞的肾脏表达得以重建。而且，VDD+IRI+R组大鼠在III型胶原蛋白量以及纤连蛋白、波形蛋白和α-SMA的肾脏表达方面表现出恢复。这些变化还伴随着肾脏中维生素D受体（VDR）、Klotho、JG12和转化生长因子-β1（TGF-β1）表达的重建。我们的研究结果表明，维生素D水平的恢复不仅改善了肾功能和血流动力学，还减少了与VDD相关的I/R-AKI中观察到的炎症和纤维化病变。因此，监测维生素D状态并在肾损伤早期进行补充可能是减轻肾脏疾病进展的一种治疗选择。
