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Stiffness sensing fuels matrix-driven metabolic reboot for kidney repair and regeneration [Visium]

ABSTRACT: Kidney repair after acute kidney injury (AKI) relies on a finely tuned extracellular matrix (ECM) that provides both structural integrity and mechanical cues. As primary ECM architects, fibroblasts and pericytes rapidly mobilize to the injury site post-AKI, yet the ECM-driven repair mechanisms remain inadequately understood. Leveraging data-independent acquisition-based proteomics, spatial transcriptomics, genetic and pharmaceutical models, and tissue engineering, we profiled the proteome landscape of decellularized kidney matrix scaffold post-AKI and highlighted microfibrillar-associated protein 2 (Mfap2) as a key core matrisome component. Sourced primarily from fibroblasts and pericytes, Mfap2 loss disrupts kidney architecture and metabolic balance, aggravating AKI. Global proteomics revealed that Mfap2 knockout downregulates tubule-derived 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) via estrogen receptor 2 (Esr2)-mediated transcriptional repression and elevated post-translational succinylation. Phosphoproteomics further uncovered a shift in mechanical signaling, where Mfap2 deficiency hyperactivates mitogen-activated protein kinases, driving large tumor suppressor kinase 1 (Lats1) in tubular cells without altering integrin receptor activity. Mechanistically, Lats1 suppression amplifies Esr2 transcription without affecting its ubiquitin-mediated degradation, functioning independently of the canonical Yap/Taz signaling. Remarkably, Esr2 agonists restored kidney function in Mfap2-deficient models. These findings position Mfap2 as a key regulator of ECM stiffness and mechanical signaling, orchestrating metabolic reprogramming and a pro-repair microenvironment essential for kidney repair and regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE299736 | GEO | 2026/01/10

REPOSITORIES: GEO

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Project description:Microarray analysis of human kidneys with acute kidney injury (AKI) has been limited because such kidneys are seldom biopsied. However, all kidney transplants experience AKI, and early kidney transplants without rejection are an excellent model for human AKI: they are screened to exclude chronic kidney disease, frequently biopsied, and have extensive follow-up. We used histopathology and microarrays to compare indication biopsies from 28 transplants with AKI to 11 pristine protocol biopsies of stable transplants. Kidneys with AKI showed increased expression of 394 injury-repair response associated transcripts, including many known epithelial injury molecules (e.g. ITGB6, LCN2), tissue remodeling molecules (e.g. VCAN), and inflammation molecules (S100A8, ITGB3). Many other genes also predict the phenotype, depending on statistical filtering rules, including AKI biomarkers as HAVCR1 and IL18. Most mouse orthologs of the top injury-repair transcripts were increased in published mouse AKI models. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score AKI kidneys correlated with reduced function, future recovery, brain death, and need for dialysis, but not future graft loss. In contrast, histologic features of "acute tubular injury" did not correlate with function or with the molecular changes. Thus the injury-repair associated transcripts represent a massive coordinate injury-repair response of kidney parenchyma to AKI, similar to mouse AKI models, and provide an objective measure for assessing the severity of AKI in kidney biopsies and validation for the use of many AKI biomarkers. AKI biopsies sample names and CEL files are from GSE21374. All consenting renal transplant patients undergoing biopsies for cause as standard of care between 09/2004 and 10/2007 at the university of Alberta or between 11/2006 and 02/2007 at the University of Illinois were included in the analysis. In addition to the cores required for standard histopathology, we collected one core for gene expression studies. the relationship between gene expression in the biopsy and subsequent graft loss was analyzed. This dataset is part of the TransQST collection.

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Stiffness sensing fuels matrix-driven metabolic reboot for kidney repair and regeneration [Visium]

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