Extracellular matrix protein 1 shapes metabolic and spatial dynamics of the kidney fibrotic microenvironment
The fibrotic kidney microenvironment is a battlefield shaped by cellular crosstalk, ECM remodeling, metabolic shifts, and spatial heterogeneity, all fueling fibrosis. In late-stage kidney disease, myofibroblast-produced ECM dominates organ function by altering bioenergetics and metabolite signaling. However, the role of early-activated matrix proteins remains unclear. This study identifies four expression patterns of core matrisome proteins, with Ecm1 emerging as a key early player in kidney remodeling. Ecm1 knockout in mice leads to spontaneous kidney fibrosis and early death, yet serum Ecm1 levels rise in CKD patients. Targeting Ecm1 via adeno-associated virus-mediated knockdown or fibroblast-specific deletion substantially reduces kidney fibrosis. Mechanistically, proteomics and spatial transcriptomics show that fibroblast-Ecm1 ablation disrupts Hippo-Yap signaling via integrin a2ß1 and RhoC in tubules, enhancing OXPHOS in tubular cells and promoting repair, as validated across pharmacological, in vivo, ex vivo, and in vitro models. Notably, diminished Hippo-Yap in fibroblasts silenced their aberrant activation without crippling their own OXPHOS. This selective ECM-mitochondrial crosstalk uncovers a mechano-metabolic pathway where mitochondrial shifts drive defense against kidney fibrosis. Overall design: Heterozygous Ecm1 mice (Product #: S-KO-01828) were obtained from Cyagen (Santa Clara, CA). Male and female Ecm1 heterozygous mice were mated to generate Ecm1-wild type (WT) and Ecm1-knockout (KO) offspring. Homozygous ECM1-floxed mice (Product #: S-CKO-02130) were also acquired from Cyagen (Santa Clara, CA). Col1a2-CreER mice (Strain #: 029567) and Pdgfrß-P2A-CreERT2 mice (Strain #: 030201) were obtained from the Jackson Laboratory (Bar Harbor, ME). By crossing Ecm1-floxed mice with Col1a2-CreER or Pdgfrß-P2A-CreERT2 transgenic mice, conditional knockout mice were generated where Ecm1 gene was specifically deleted in kidney Col1a2+ or Pdgfrß+ fibroblasts (genotype: ECM1fl/fl, Cre ±) were created. These conditional knockouts were bred with homozygous Ecm1-floxed mice (genotype: ECM1fl/fl), yielding litters with 50% Col1a2-Ecm1-/- or Pdgfrß-Ecm1-/- mice and 50% control mice (Col1a2-Ecm1+/+ or Pdgfrß-Ecm1+/+). Kidney ECM1 WT slide and ECM1 KO slide were pooled into one spatial transcritpomics imaging for analysis.