Although coronavirus disease 2019 (COVID-19) causes significan t morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major componen ts of the disease. Kidney disease, usually presenting as AKI, is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-19’s causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms.

Using ex vivo cell models, we sought to analyze SARS-CoV-2 interactions with kidney tubular cells and assess direct tubular injury. These models comprised primary human kidney epithelial cells (derived from nephrectomies) and grown as either proliferating monolayers or quiescent three-dimensional kidney spheroids.

We demonstrated that viral entry molecules and high baseline levels of type 1 IFN–related molecules were present in monolayers and kidney spheroids. Although both models support viral infection and replication, they did not exhibit a cytopathic effect and cell death, outcomes that were strongly present in SARS-CoV-2–infected controls (African green monkey kidney clone E6 [Vero E6] cultures). A comparison of monolayer and spheroid cultures demonstrated higher infectivity and replication of SARS-CoV-2 in actively proliferating monolayers, although the spheroid cultures exhibited high er levels of ACE2. Monolayers exhibited elevation of some tubular injury molecules—including molecules related to fibrosis (COL1A1 and STAT6) and dedifferentiation (SNAI2)—and a loss of cell identity, evident by reduction in megalin (LRP2). The three-dimensional spheroids were less prone to such injury.

SARS-CoV-2 can infect kidney cells without a cytopathic effect. AKI-induced cellular proliferation may potentially intensify infectivity and tubular damage by SARS-CoV-2, suggesting that early intervention in AKI is warranted to help minimize kidney infection.

尽管 2019 年冠状病毒病 (COVID-19) 会导致显着的发病率（主要是肺部受累），但肺外症状也是该疾病的主要组成部分。肾脏疾病通常表现为 AKI，在 COVID-19 患者中尤为严重。然而，目前尚不清楚这种损伤是由 COVID-19 致病病毒、严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的直接肾脏感染引起，还是由间接机制引起。

使用离体细胞模型，我们试图分析 SARS-CoV-2 与肾小管细胞的相互作用并评估直接肾小管损伤。这些模型由原代人肾上皮细胞（源自肾切除术）组成，并生长为增殖单层或静止三维肾球体。

我们证明，单层细胞和肾球体中存在病毒进入分子和高基线水平的 1 型干扰素相关分子。尽管这两种模型都支持病毒感染和复制，但它们没有表现出细胞病变效应和细胞死亡，而这些结果在 SARS-CoV-2 感染的对照（非洲绿猴肾克隆 E6 [Vero E6] 培养物）中强烈存在。单层和球状培养物的比较表明，尽管球状培养物表现出更高水平的 ACE2，但活跃增殖的单层细胞中 SARS-CoV-2 的感染性和复制性更高。单层细胞表现出一些肾小管损伤分子的升高，包括与纤维化（COL1A1和STAT6）和去分化（SNAI2）相关的分子，以及细胞身份的丧失，这通过巨蛋白（LRP2）的减少来证明。三维球体不太容易受到这种伤害。

SARS-CoV-2 可以感染肾细胞，但不会产生细胞病变效应。 AKI 诱导的细胞增殖可能会加剧 SARS-CoV-2 的感染性和肾小管损伤，这表明需要对 AKI 进行早期干预，以帮助最大限度地减少肾脏感染。