Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration

Abstract

The kidney has tremendous capacity to repair after acute injury, however, pathways guiding adaptive and fibrotic repair are poorly understood. We developed a model of adaptive and fibrotic kidney regeneration by titrating ischemic injury dose. We performed detailed biochemical and histological analysis and profiled transcriptomic changes at bulk and single-cell level (> 110,000 cells) over time. Our analysis highlights kidney proximal tubule cells as key susceptible cells to injury. Adaptive proximal tubule repair correlated with fatty acid oxidation and oxidative phosphorylation. We identify a specific maladaptive/profibrotic proximal tubule cluster after long ischemia, which expresses proinflammatory and profibrotic cytokines and myeloid cell chemotactic factors. Druggability analysis highlights pyroptosis/ferroptosis as vulnerable pathways in these profibrotic cells. Pharmacological targeting of pyroptosis/ferroptosis in vivo pushed cells towards adaptive repair and ameliorates fibrosis. In summary, our single-cell analysis defines key differences in adaptive and fibrotic repair and identifies druggable pathways for pharmacological intervention to prevent kidney fibrosis.

Spatially resolved human kidney multi-omics single cell atlas highlights the key role of the fibrotic microenvironment in kidney disease progression

“…Previous single cell analyses, focusing on dissociated human and mouse kidney datasets, have generated gene expression and regulatory matrices for a variety of kidney cell types (8)(9)(10)(11)(12)37). As kidney cell types have been functionally well characterized, most identified cell types have been matched back to a more than half-century old functional cell type definition (6).…”

“…More than 30 specialized cell types including epithelial, endothelial, interstitial and immune cells have been identified in the kidney (6,7). The development of novel single cell and single nuclear RNA-sequencing (scRNA-seq, snRNA-seq, respectively) as well as single nuclei Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) have provided an unprecedented insight into the molecular and cellular composition of healthy mouse and human kidneys as well as changes during development and disease (8)(9)(10)(11)(12). These methods use dissociated cells or nuclei isolated from kidney tissue samples.…”

Physiological Effects of Ferroptosis on Organ Fibrosis

“…However, the application of single-cell omics provides a good shortcut. A single-cell analysis has now shown that 11 Oxidative Medicine and Cellular Longevity ferroptosis and pyroptosis activate inflammatory cells and promote fibrosis development in PT cells [110]. Undoubtedly, with the application of single-cell omics, more drugs and their mechanisms of interfering with ferroptosis will be discovered, which will be of great benefit to patients with CKD.…”

Inflammation-mediated Upregulation of VCAM-1 but not KIM-1 during Acute Kidney Injury to Chronic Kidney Disease Transition

“…Their activation is responsible for recruiting a second wave of immune cell infiltration into the unresolved kidneys. The persistence of interstitial immune cells in turn promotes kidney fibrosis and inflammation, which lead to CKD transition (11)(12)(13)(14)(15).…”