SLC39A8-mediated zinc dyshomeostasis potentiates kidney disease
Abstract
While numerous genetic risk loci are linked to kidney disease, a unifying therapeutic target for diverse renal pathologies remains elusive. Here, through large-cohort polymorphic locus screening, we identify the SLC39A8 A391T variant (rs13107325) as a shared modifier of multiple kidney diseases. Functional characterization using Slc39a8 A391T knock-in mice and kidney-specific Slc39a8 knockout mice reveals that loss of SLC39A8 function reduces renal zinc accumulation, thereby mitigating susceptibility to kidney injury and disease progression. Mechanistically, we demonstrate that perturbed zinc homeostasis drives renal damage, and limiting zinc levels—whether via impaired SLC39A8 activity or direct chelation—activates the zinc–AKT–FOXO1–G6PC axis to confer protection. Critically, zinc chelation with EDTA recapitulates this benefit, significantly preventing and ameliorating experimental acute and chronic kidney disease. These findings establish renal zinc homeostasis as a key therapeutic node, with SLC39A8 and zinc-modulating strategies representing promising avenues for treating a broad range of kidney diseases.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (12)
Zhaoxian Cai
The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine
Xiaotian Wu
The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine
Tianyi Wang
Advanced Institute for Materials Research (WPI-AIMR)
Zijun Song
The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine
Pu Ni
The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine
Meijuan Zhong
School of Public Health, Basic Medical Sciences, The First Affiliated Hospital, Hengyang Medical School, University of South China
Yunxing Su
The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine
Enjun Xie
The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine
Shumin Sun
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices
Yangjun Lin
The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine
Junxia Min
The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine
Fudi Wang
The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine