Meprin β Mediates Renal Fibrosis and Dysfunction in Tubule-Specific ADAM10/17 Dual Deletion

A disintegrin and metalloproteinases 10 and 17 (ADAM10/17) cleave a broad range of transmembrane proteins, generating bioactive fragments that influence renal development, homeostasis, and inflammatory responses. Dysregulated ADAM10 activity has been linked to lupus nephritis, arterionephrosclerosis, and diabetic nephropathy, whereas aberrant ADAM17 function contributes to tubular atrophy and interstitial fibrosis. These associations have prompted interest in selectively inhibiting ADAM10/17 as a therapeutic strategy. However, broad-spectrum metalloproteinase inhibitors have shown limited clinical benefit due to off-target effects and the complex, context-dependent roles of ADAM10/17 in renal physiology. Furthermore, the in vivo consequences of ADAM10/17 loss specifically within renal tubular cells remain insufficiently defined. To address this gap, we generated renal tubular cell (RTC)–specific ADAM10/17 double-knockout (cDKO) mice and compared renal function, metabolic parameters, urinary electrolyte and protein excretion, and kidney histopathology with wild-type (WT) controls. The cDKO mice exhibited pronounced tubular injury and increased collagen deposition, accompanied by reduced glomerular filtration rate, impaired urinary sodium and potassium excretion, and decreased creatinine and urea clearance. Mechanistically, ADAM10/17 deficiency upregulated key sodium transporters (Slc34a1, NCC, pNCC) and the water channel AQP1, indicating enhanced tubular sodium and water reabsorption. Proteomic profiling revealed broad dysregulation of metabolic and fibrotic pathways, particularly those involving PPAR and TGF-β signaling. Among the differentially expressed proteins between cDKO and WT kidneys, Mep1b emerged as a markedly downregulated ADAM10/17 substrate, a finding further validated by western blot and immunohistochemistry. Remarkably, renal administration of recombinant Mep1b restored renal structure and function, improved urinary electrolyte excretion in cDKO mice, and normalized ADAM10, TNF-α, pNCC, and Slc34a1 levels in cDKO-RTCs. Collectively, these findings provide the first in vivo evidence that Mep1b is a key downstream mediator of the ADAM10/17 signaling axis in renal tubular cells and highlight its therapeutic potential for reversing the renal injury and dysfunction resulting from ADAM10/17 deficiency. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.