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

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. Overall design: Heterozygous Mfap2 mice (Product name: S-KO-03113, Strain name: C57BL/6JCya-Mfap2em1) were obtained from Cyagen (Santa Clara, CA). Male and female Mfap2 heterozygous mice were mated to generate Mfap2-wild type (WT) and Mfap2-knockout (KO) offspring. Kidney MFAP2 WT slide and MFAP2 KO slide were pooled into one spatial transcritpomics imaging for analysis.