Single-cell sequencing reveals homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced AKI

Abstract

Homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced acute kidney injury (AKI) are poorly understood. Here, we performed single-cell sequencing (scRNA) on mouse kidneys with five common AKI etiologies (CP-Cisplatin, IRI-Ischemia-reperfusion injury, UUO-Unilateral ureteral obstruction, FA-Folic acid, and SO-Sodium oxalate). We constructed a potent multi-model AKI scRNA atlas containing 20 celltypes with 80,689 high-quality cells. The data suggest that compared to IRI and CP-AKI, FA- and SO-AKI exhibit injury characteristics more similar to UUO-AKI, which may due to tiny crystal-induced intrarenal obstruction. Through scRNA atlas, 7 different functional proximal tubular cell (PTC) subtypes were identified, we found that Maladaptive PTCs and classical Havcr1 PTCs but not novel Krt20 PTCs affect the pro-inflammatory and pro-fibrotic levels in different AKI models. And cell death and cytoskeletal remodeling events are widespread patterns of injury in PTCs. Moreover, we found that programmed cell death predominated in PTCs, whereas apoptosis and autophagy prevailed in the remaining renal tubules. We also identified S100a6 as a novel AKI-endothelial injury biomarker. Furthermore, we revealed that the dynamic and active immune (especially Arg1 Macro_2 cells) -parenchymal cell interactions are important features of AKI. Taken together, our study provides a potent resource for understanding the pathogenesis of AKI and early intervention in AKI progression at single-cell resolution.

Gclc as a Marker for Injured Distal Nephron in Ischemia-Reperfusion Induced Acute Kidney Injury

“…Due to the significant increase in ferroptosis levels in IR and the subsequent increase observed in UUO, as shown in the study by Zhimin Chen et al, 20 we established mouse models for both IR and UUO at 1 day, 7 days, and 14 days. In IR, we noted a gradual worsening of renal injury and fibrosis over time, along with a significant increase for ACSL4 as early as IR D1 ( Supplementary Figure S3A ).…”

“…18 Bone marrow mesenchymal stem cells that overexpress GCLC was found to alleviate acute lung injury through anti-apoptotic effects. 19 In this study, the transcriptional characteristics of distal renal tubules in various AKI models were analyzed using scRNA-seq data from Zhimin Chen et al 20 The marker Gclc of the distal renal tubule was identified through scRNA-seq and renal transcriptomics data. Furthermore, the role of Gclc in acute kidney injury was explored by targeting Gclc.…”

H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells

“…Several reports suggest that ferroptosis may promote cellular susceptibility to apoptosis, and the damaged mitochondria and lipid peroxide from ferroptosis would initiate and drive apoptotic signals [ 37 , 49 ]. Single cell sequencing demonstrated that both ferroptotic and apoptotic proteins could be changed simultaneously in the same cells [ 50 ]. This evidence points to the complexity of cell fate under different disease conditions.…”

Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis

“…Moreover, in the UUO model there is no tubular recovery, so it is not an ideal model to study tubular injury and repair. Also, the precise cytopathological mechanisms driving UUO-induced renal injury are poorly understood ( 35 ). In addition, fibrosis develops very rapidly in the model, which limits the experimental window for testing potential ameliorating interventions unless they are introduced before the UUO injury or are expected to have profound effects ( 36 , 37 ).…”