| Autor: |
Wen, Yumeng, Su, Emily, Xu, Leyuan, Menez, Steven, Moledina, Dennis G., Obeid, Wassim, Palevsky, Paul M., Mansour, Sherry G., Devarajan, Prasad, Cantley, Lloyd G., Cahan, Patrick, Parikh, Chirag R. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 12/13/2023, Vol. 15 Issue 726, p1-15, 15p |
| Abstrakt: |
Acute kidney injury (AKI) is a major risk factor for long-term adverse outcomes, including chronic kidney disease. In mouse models of AKI, maladaptive repair of the injured proximal tubule (PT) prevents complete tissue recovery. However, evidence for PT maladaptation and its etiological relationship with complications of AKI is lacking in humans. We performed single-nucleus RNA sequencing of 120,985 nuclei in kidneys from 17 participants with AKI and seven healthy controls from the Kidney Precision Medicine Project. Maladaptive PT cells, which exhibited transcriptomic features of dedifferentiation and enrichment in pro-inflammatory and profibrotic pathways, were present in participants with AKI of diverse etiologies. To develop plasma markers of PT maladaptation, we analyzed the plasma proteome in two independent cohorts of patients undergoing cardiac surgery and a cohort of marathon runners, linked it to the transcriptomic signatures associated with maladaptive PT, and identified nine proteins whose genes were specifically up- or down-regulated by maladaptive PT. After cardiac surgery, both cohorts of patients had increased transforming growth factor–β2 (TGFB2), collagen type XXIII-α1 (COL23A1), and X-linked neuroligin 4 (NLGN4X) and had decreased plasminogen (PLG), ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6), and protein C (PROC). Similar changes were observed in marathon runners with exercise-associated kidney injury. Postoperative changes in these markers were associated with AKI progression in adults after cardiac surgery and post-AKI kidney atrophy in mouse models of ischemia-reperfusion injury and toxic injury. Our results demonstrate the feasibility of a multiomics approach to discovering noninvasive markers and associating PT maladaptation with adverse clinical outcomes. Editor's summary: Although acute kidney injury (AKI) commonly affects hospitalized patients and is associated with adverse outcomes, it has been understudied in humans. Here, Wen and colleagues integrated single-nucleus RNA sequencing data from human kidney biopsy specimens with plasma proteomic data to identify markers of proximal tubule maladaptation and markers of proximal tubule healthy states. They validated these markers in independent patient cohorts and in mouse models of ischemia-reperfusion injury and aristolochic acid–induced nephropathy. This study suggests that proximal tubule maladaptation occurs in response to injury from a number of causes and identifies markers of proximal tubule health and disease, which may be useful for both prognostic and drug development purposes. —Melissa L. Norton [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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