Among the various aspects of the present disclosure is the provision of methods and compositions to treat or prevent an endoplasmic reticulum (ER) stress-mediated kidney disease in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an ER calcium channel stabilizing agent or an ER stress modulating agent (e.g., mesencephalic astrocyte-derived neurotrophic factor (MANF), compound K201).