Kidney Organoids as a Novel Platform to Evaluate Lipopolysaccharide-Induced Oxidative Stress and Apoptosis in Acute Kidney Injury.

Weitao Zhang,Xuepeng Zhang,Tingting Li,Yi Shi,Ruochen Qi,Ming Xu,Tongyu Zhu

doi:10.3389/fmed.2021.766073

Abstract

Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening syndrome. Lipopolysaccharide (LPS) is a widely used inducer for modeling SA-AKI both in vivo and in vitro. However, due to the innate complexity of the kidney architecture, the mechanisms underlying the pathogenesis of SA-AKI, as well as those involved in LPS-induced kidney injury remain to be clarified. Kidney organoids derived from human pluripotent stem cells (hPSCs) act as a model of multiple types of kidney cells in vitro and eliminate potential confounders in vivo. In the current study, we established LPS-induced kidney injury models both in vivo and in human kidney organoids. Kidney function, pathological changes, and markers of oxidative stress were evaluated with/without the presence of methylprednisolone (MP) treatment both in vivo and in vitro. The extent of LPS-induced oxidative stress and apoptosis in kidney organoids was further investigated in vitro. LPS-induced acute kidney injury in mice, together with pathological changes and increased oxidative stress, as well as enhanced apoptosis in kidney cells were evaluated. These phenomena were ameliorated by MP treatment. Experiments in kidney organoids showed that the LPS-induced apoptotic effects occurred mainly in podocytes and proximal tubular cells. Our experiments demonstrated the efficacy of using kidney organoids as a solid platform to study LPS-induced kidney injury. LPS induced oxidative stress as well as apoptosis in kidney cells independently of changes in perfusion or immune cell infiltration. MP treatment partially alleviated LPS-induced injury by reducing kidney cell oxidative stress and apoptosis.

Highlights

Sepsis is characterized by a set of clinical syndromes caused by the dysregulated host response to infection and is manifested by organ dysfunction, according to the definition of the Third International Consensus (Sepsis-3) [1, 2]
The evaluation of the blood samples showed that the serum creatinine level and blood urine nitrogen (BUN) levels continued to increase after LPS injection and reached a peak at 24 h after induction (Figures 1A,B), FIGURE 1 | Lipopolysaccharide (LPS) induces acute kidney injury (AKI) in mice and was ameliorated by methylprednisolone (MP) treatment. (A) Serum creatinine levels and (B) serum blood urine nitrogen (BUN) levels of mice treated with LPS for different periods. (C) Serum creatinine levels and (D) serum BUN levels of mice treated with LPS and MP. *P < 0.05, **P < 0.01, ***P < 0.001
The MP treatment partially rescued the LPS-induced apoptotic effects again. These findings suggested that LPS-induced apoptosis occurred primarily in podocytes and proximal tubular cells

Summary

Introduction

Sepsis is characterized by a set of clinical syndromes caused by the dysregulated host response to infection and is manifested by organ dysfunction, according to the definition of the Third International Consensus (Sepsis-3) [1, 2]. The kidney is one of the most vulnerable organs affected during the progression of Kidney Organoids for LPS-Induced AKI sepsis. Sepsis-associated acute kidney injury (SA-AKI), like acute kidney injury (AKI) due to other causes, is characterized by an increase in serum creatinine levels and/or by a decrease in urine volume [2,3,4]. Owing to shared pathophysiological mechanisms, sepsis and AKI are inseparable and should be considered as integral entities in the clinical setting. It is of great importance to explore the innate mechanism of SA-AKI and to provide evidence for treatment in the clinical setting

Methods

Results

Conclusion