Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.

Department of Biomedical Engineering School of Engineering and Applied Science Washington University St Louis MO USA

Department of Cell Biology and Physiology Washington University School of Medicine St Louis MO USA

Department of Chemistry Washington University St Louis MO USA

Department of Neurology Washington University School of Medicine St Louis MO USA

Division of Endocrinology Metabolism and Lipid Research Department of Medicine Washington University School of Medicine St Louis MO USA

Division of Nephrology Department of Medicine Washington University School of Medicine St Louis MO USA

Genome Technology Access Center McDonnell Genome Institute Washington University School of Medicine St Louis MO USA

Institute of Biotechnology HiLIFE University of Helsinki Helsinki Finland

Mallinckrodt Institute of Radiology Washington University School of Medicine St Louis MO USA

Nutrition and Geriatrics Division Washington University School of Medicine St Louis MO USA

Pfizer Worldwide Research and Development Inflammation and Immunology Cambridge MA USA

Prime Medicine Inc Cambridge MA USA

Research Unit of Rare Diseases Department of Pediatric and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague Czech Republic

Section of Nephrology Wake Forest University School of Medicine Winston Salem NC USA

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$a Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.

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