The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain-containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD-UMOD, and in mutant-UMOD-knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.

Departamento de Nefrología y Metabolismo Mineral Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Ciudad de México México

Department of Anatomy Charité Universitätsmedizin Berlin Germany

Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

Department of Nephrology and Medical Intensive Care Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany

Department of Pathology Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

Division of Nephrology Beth Israel Deaconess Medical Center and Department of Medicine Harvard Medical School Boston Massachusetts USA

Institute of Physiology Christian Albrechts Universität Kiel Germany

Institute of Translational Physiology and

Proteomics Platform The Broad Institute of MIT and Harvard Cambridge Massachusetts USA

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

Section on Nephrology Wake Forest School of Medicine Medical Center Blvd Winston Salem North Carolina USA

The Broad Institute of Massachusetts Institute of Technology and Harvard Cambridge Massachusetts USA

The Mina and Everard Goodman Faculty of Life Sciences Bar Ilan University Ramat Gan Israel

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