Extracellular Matrix Stiffness determines kidney metabolism reprogramming after AKI

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.