Proximal tubule responses to injury: interrogation by single-cell transcriptomics

Abstract

Purpose of reviewAcute kidney injury (AKI) occurs in approximately 10--15% of patients admitted to hospital and is associated with adverse clinical outcomes. Despite recent advances, management of patients with AKI is still mainly supportive, including the avoidance of nephrotoxins, volume and haemodynamic management and renal replacement therapy. A better understanding of the renal response to injury is the prerequisite to overcome current limitations in AKI diagnostics and therapy. Recent findingsSingle-cell technologies provided new opportunities to study the complexity of the kidney and have been instrumental for rapid advancements in the understanding of the cellular and molecular mechanisms of AKI.

A transfer learning framework to elucidate the clinical relevance of altered proximal tubule cell states in kidney disease

“…The injured PT cell states identified in those patients shared the main features previously characterized in experimental models of ischemic AKI in mice, including the loss of physiological tubule functions and fundamental changes in energy metabolism and the activation of genes related to cell-matrix interaction and tubule development. 8 , 10 , 14 Injured PT cells activated the main signaling pathways known to be involved in CKD progression, such as TGFβ, NF-κB, TNFα, and WNT, consistently with their role in the generation of the niche . 11 The observation that the main biological processes of AKI are conserved across species is in line with our previous studies based on bulk RNAseq.…”

“…The cellular response to kidney injury has been extensively investigated in the last years, particularly in the PT. 14 In animal models, single cell technologies allowed a precise characterization of the dynamic PT cell state transitions, starting from the early phase of cell dedifferentiation and death, to the activation of a reparative program including cell proliferation and re-differentiation. 9 , 10 This complex biological process can restore tubular structures and functions, but can also result in a maladaptive response leading to the persistence of altered epithelial cells, which acquire a squamous epithelium morphology and maintain a dedifferentiated cell state.…”

“… 4 , 5 , 6 , 7 , 8 , 9 , 10 Evidence from experimental models suggests that altered tubule cells interact with surrounding cells to form cell communities involved in chronic inflammation and fibrosis, eventually leading to irreversible damage and CKD progression. 11 , 12 , 13 , 14 The relevance of those findings needs to be validated in patients. 14 …”

Stepwise developmental mimicry generates proximal-biased kidney organoids

“…Future experiments are required to assess the regenerative potential of these organoids under prolonged culture conditions and to determine the timeline and extent of possible recovery following repeated cisplatin treatment. Developing a tightly controlled synchronized injury model suitable for posing precise questions on the impact of compounds – such as chemotherapeutics, antibiotics, or other agents – is of high clinical value and would allow scrutiny of transition states that proximal nephron cells undergo post-injury 80 .…”