Ying Maggie Chen Lab and Collaborators Uncover Biotherapeutic Properties of MANF Protein

Ying Maggie Chen led study on MANF protein

In their newly-published article in Nature Communications, a multi-center group led by Ying Maggie Chen, MD, PhD, WashU Division of Nephrology, describes previously unknown mechanisms of action of mesencephalic astrocyte-derived neurotrophic factor (MANF) and its therapeutic function, with regards to kidney disease.  MANF is a secreted endoplasmic reticulum (ER) protein that possesses cytoprotective properties. Their findings have profound therapeutic potential to ameliorate kidney fibrosis and slow kidney function decline in ADTKD-UMOD (autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations), US patent 11,129,871. 

Misfolded proteins due to genetic mutations and the resultant ER stress represent one important cause of ER storage disease and toxic proteinopathy, including ADTKD-UMOD, a leading hereditary kidney disease that causes renal fibrosis.  Unfortunately, the molecular link between ER stress activation and renal fibrosis is not clear and there are no targeted therapies.

The group generated the first Umod deletion mutation mouse model of human ADTKD-UMOD and employed both loss- and gain-of-function studies of MANF.  They found that deletion of MANF worsened autophagy failure and renal fibrosis and that overexpression of MANF improved autophagy and mitochondrial function, as well as inhibited mitochondria-dependent inflammation, thus attenuating kidney injury and fibrosis.

Overall, their findings reveal an important therapeutic function of MANF by regulating organelle homeostasis for the treatment of ADTKD and possibly other toxic proteinopathies such as Alzheimer’s disease, amyotrophic lateral sclerosis, and Wolfram syndrome,.

The article, “MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice,” which can be read here, was recently highlighted in the ASN In the Loop newsletter. 

Members of the Chen lab, Yeawon Kim and Chuang Li, Postdoc Research Associate, are co-first authors of the article.  “Chenjian Gu and Yili Fang, two outstanding Postdocs in the Chen lab, also made great contributions to the project,” says Dr. Chen.

Yeawon Kim
Chuang Li

The project also involved multiple national and international labs.  Vijay Sharma, PhD, Professor of Radiology, WashU, was instrumental in performing the PET/CT imaging studies.  Anthony Bleyer, MD, at Wake Forest School of Medicine, an international leader in ADTKD provided patient materials.