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Abstract: TH-OR079

Lysosomal β-Mannosidase (Manba) Is a CKD Risk Gene

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Gu, Xiangchen, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Yang, Hongliu, West China Hospital of Sichuan University, Chengdu, sichuan, China
  • Qiu, Chengxiang, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Park, Jihwan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Huang, Shizheng, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the population worldwide. Through the computational integration of CKD genome-wide association study (GWAS) variants and kidney compartment-based expression of quantitative trait loci (eQTLs) analysis, we identified lysosomal β-Mannosidase(Manba) as a candidate CKD risk gene. Manba is a lysosomal glycosyl hydrolase. Here we studied mice with genetic manipulation of Manba to understand the role of Manba in CKD.

Methods

We generated gene expression and genotype information and conducted eQTLs analysis on 121 microdissected human kidney glomerular and tubule samples. Bayesian colocalization method was performed to integrate the GWAS and eQTL data. We performed single cell RNA-sequencing on healthy mouse kidneys. We generated Manba knock-out mice and induced kidney disease by aging or by folic acid injection. We examined renal histology and gene expression. We analyzed lysosomes and autophagy in vivo and in cultured tubular epithelial cells in vitro.

Results

EQTLs analysis indicated that in human kidney tissue samples with CKD risk variant, the expression of Manba was significantly lower when compared to the reference allele kidneys. Manba was mostly expressed in kidney tubule cells including proximal tubules and principal cells in the mouse kidney single cell dataset. Double immunofluorescence staining confirmed its expression pattern. Aging (at 70 weeks age) Manba knock-out mice exhibited an increase in numbers of lysosomes and autophagic vacuoles in tubular cells. In FA-induced kidney fibrosis model, Manba knock-out mice showed more severe fibrotic changes by histological analysis and an increase in profibrotic genes by QRT-PCR. Manba knock-out mice and cultured Manba knock-out tubular cells demonstrated altered lysosomal dynamics. As lysosomes play a key role in autophagy, Manba knock-out mice also showed lower autophagic flux.

Conclusion

Taken together, these findings indicate that Manba is a CKD risk gene. Manba deficiency exacerbates kidney fibrosis, likely via lysosomal alterations and an impaired autophagic clearance.

Funding

  • NIDDK Support