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Chronic diseases, also known as non-communicable diseases (NCD), represent a growing burden to the worldwide community. The 2030 Agenda for Sustainable Development recognizes NCD as a major challenge for sustainable development. Indeed, many of the risk factors that influence chronic diseases progression represent current worldwide challenges such us pollution, climate changes, gender-based differences, progressive population ageing and genetic factors. Unlike many other NCD, chronic kidney disease (CKD) burden has not declined to the same extent implying a substantial deficit in the understanding of its progression. In addition, CKD patients experience a progressive loss of kidney function and have a high risk of progression towards end stage kidney disease (ESKD). ESKD requires kidney replacement therapy in the form of dialysis or kidney transplantation, both of which carry a significant economic and environmental burden. Moreover, the costs associated with these replacement therapies are high, and in most countries, economic constraints allow only restricted access to this expensive chronic treatment, with striking social inequalities. For this reason, there is an urgent need to identify, tackle and prevent the factors that contribute to kidney function decline and ultimately CKD progression. Recently, we have shown that polyploidization of tubular cells (TC) is triggered by acute kidney injury (AKI) to allow survival in the early phase after AKI, but in the long run promotes fibrosis and AKI-chronic kidney disease (CKD) transition. Polyploid cells are hypertrophic cells characterized by increased DNA content. The molecular mechanism governing the link between polyploid TC and kidney fibrosis remains to be clarified.
To address this link, we used the cutting edge technology of single-cell RNA sequencing in combination with transgenic mouse models and in vitro models based on the Fucci2aR reporter.
We demonstrated that immediately after AKI, expression of cell cycle markers mostly identifies a population of DNA-damaged polyploid TC. Unlike diploid TC, polyploid TC accumulate DNA damage and survive, eventually resting in the G1 phase of the cell cycle. In vivo and in vitro single-cell RNA sequencing along with sorting of polyploid TC shows that these cells acquire a profibrotic phenotype culminating in transforming growth factor (TGF)-β1 expression and that TGF-β1 directly promotes polyploidization. This demonstrates that TC polyploidization is a self-sustained mechanism. Interactome analysis by single-cell RNA sequencing revealed that TGF-β1 signaling fosters a reciprocal activation loop among polyploid TC, macrophages, and fibroblasts to sustain kidney fibrosis and promote CKD progression.
Collectively, this study contributes to the ongoing revision of the paradigm of kidney tubule response to AKI, supporting the existence of a tubulointerstitial cross talk mediated by TGF-β1 signaling produced by polyploid TC following DNA damage. This acquired knowledge can be exploited to identify novel biomarkers to prevent CKD development and devise novel compounds to slow down CKD progression.