Activating Autophagy to Treat Uromodulin-Associated Genetic Chronic Kidney Disease

Uromodulin-associated genetic chronic kidney disease, or autosomal dominant tubulointerstitial kidney disease caused by uromodulin mutations (ADTKD-UMOD), is a leading hereditary kidney disease and characterized by renal fibrosis and progressive loss of kidney function. Currently there is no targeted therapy. To address the unmet medical needs, by using CRISPR/Cas9, we have developed an ADTKD-UMOD mouse model carrying Umod p.Tyr178-Arg186 del, the mouse equivalent of the most prevalent human mutation. Uromodulin (UMOD) is mostly synthesized and secreted by the tubular cells of thick ascending limb (TAL). Linked with mutant UMOD-triggered endoplasmic reticulum (ER) stress, our mouse model shows that autophagy and mitophagy deficiency in TALs leads to increased accumulation of the toxic mutant UMOD aggregates and mitochondrial DNA leakage-induced activation of innate immune signaling molecule STING (stimulator of interferon genes), which cause TAL cell death and renal fibrosis in ADTKD. Most importantly, we have discovered a novel ER soluble protein mesencephalic astrocyte-derived neurotrophic factor (MANF), which functions as a positive regulator of autophagy/mitophagy. MANF tubular overexpression can decrease mutant UMOD accumulation and counteract STING-induced inflammation, thus attenuating fibrosis and improving kidney function in our mouse model of ADTKD. Our hypothesis is that restoring suppressed autophagy and mitophagy by targeting MANF and its receptor is a novel therapeutic strategy to treat ADTKD-UMOD. The overall goals of this proposal are to determine the molecular mechanisms underpinning the biological and therapeutic functions of MANF, to develop MANF-based therapy, and to define the role of newly identified MANF receptor neuroplastin in ADTKD. To accomplish our research goals, we have assembled an interdisciplinary team including multiple Co-Investigators and cores with various innovative technologies and required expertise. The proposed study will provide critical insights into the molecular pathogenesis of ADTKD and develop highly-targeted and mechanism-based novel treatments for ADTKD patients.