Therapeutic Targeting of Mitochondria in Uromodulin-Associated Chronic Kidney Disease

Uromodulin (UMOD)-associated chronic kidney disease (CKD), or autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations (ADTKD-UMOD), is characterized by progressive renal fibrosis and CKD. Currently there is no targeted therapy. The disease is frequently manifested until adulthood and its prevalence

has been significantly underestimated in Veterans. Moreover, genetic variants in the UMOD locus have the largest effect on kidney function and CKD progression in both general population and Veterans, and UMOD genetic variants with unknown function have also been identified with high frequency in hypertensive and

diabetic kidney disease, the most common causes of CKD and kidney failure among Veterans and the general American population. However, the functional significance of these UMOD variants remains elusive. Thus, our research on the UMOD genetic variants will contribute to the improvement of Veteran’s health significantly.

To address the unmet medical needs, by using CRISPR/Cas9 we have developed a mouse model carrying Umod p.Tyr178_Arg186 del, the mouse equivalent of the most prevalent human mutation. UMOD is primarily synthesized and secreted by the tubular cells of thick ascending limb (TAL) of Henle’s loop. We demonstrate

that defective mitochondrial biogenesis, oxidative phosphorylation (OXPHOS) and mitophagy in the mutant TALs lead to activation of STING (stimulator of interferon genes)-mediated inflammation, eventually causing TAL cell death and renal fibrosis. More importantly, we have discovered a novel biotherapeutic protein,

mesencephalic astrocyte-derived neurotrophic factor (MANF) that can positively modulate mitochondrial quality control and mitigate STING-induced inflammation and fibrosis in our ADTKD mouse model. Additionally, we provide compelling data that blockade of MANF receptor neuroplastin preserves mitochondrial function and

that inhibition of the STING pathway suppresses mitochondria-dependent inflammation in our mutant UMOD cell model. The overall goal of this VA Merit application is to develop novel therapies to restore mitochondrial function and alleviate mitochondria-mediated inflammation by targeting MANF and neuroplastin, as well as STING

pathway in ADTKD. Our overarching hypothesis is that promoting mitochondrial homeostasis is a novel therapeutic strategy to treat ADTKD-UMOD and CKD. To accomplish our research goals and test our hypothesis, 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 other forms of organelle stress-induced CKD, as well as discover mitochondria-targeted and mechanism-based novel treatments for ADTKD and CKD in Veterans.