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Extracellular Matrix Stiffness determines kidney metabolism reprogramming after AKI

ABSTRACT: Kidney repair after acute kidney injury (AKI) relies on a well-regulated extracellular matrix (ECM) that provides structural and mechanical cues. Fibroblasts and pericytes, key ECM producers, are rapidly activated post-injury, but ECM-driven repair mechanisms remain unclear. Using proteomics, spatial transcriptomics, and animal models, we profiled the landscape of matrix proteins altered post-AKI, highlighting microfibrillar-associated protein 2 (Mfap2) as a critical ECM component. Predominantly derived from fibroblasts and pericytes, Mfap2 loss impairs kidney architecture and metabolism, worsening AKI. Proteomics revealed that Mfap2 knockout suppresses tubule-derived Hmgcs2 via Esr2-mediated transcriptional repression and enhanced succinylation. Phosphoproteomics showed Mfap2 deletion hyperactivates MAPK and Lats1 in tubules, independent of integrin signaling and Yap/Taz. Mechanistically, reduced Lats1 boosts Esr2 transcription without affecting its degradation. Esr2 agonists restored kidney function in Mfap2-deficient models. Thus, Mfap2 governs ECM stiffness, transduces mechanical signals, reprograms metabolism, and fosters a pro-repair microenvironment critical for AKI recovery.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

SUBMITTER: Wenxue Li

LAB HEAD: Yansheng Liu

PROVIDER: PXD064267 | Pride | 2025-12-23

REPOSITORIES: Pride

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			Action	DRS
	20240315_Dong_Zhou_kidney_phospho_KO_G1134.raw	Raw
	20240315_Dong_Zhou_kidney_phospho_KO_G1135.raw	Raw
	20240315_Dong_Zhou_kidney_phospho_KO_G1136.raw	Raw
	20240315_Dong_Zhou_kidney_phospho_KO_G1137.raw	Raw
	20240315_Dong_Zhou_kidney_phospho_KO_G1138.raw	Raw

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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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Extracellular Matrix Stiffness determines kidney metabolism reprogramming after AKI

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