1. Tauroursodeoxycholic acid ameliorates renal injury induced by COL4A3 mutation.
- Author
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Yu S, Gu X, Zheng Q, Liu Y, Suhas T, Du W, Xie L, Fang Z, Zhao Y, Yang M, Xu J, Wang Y, Lin MH, Pan X, Miner JH, Jin Y, and Xie J
- Subjects
- Animals, Humans, Male, Mice, Apoptosis drug effects, Autoantigens genetics, Autoantigens metabolism, Disease Models, Animal, Kidney pathology, Kidney drug effects, Kidney metabolism, Mice, Inbred C57BL, Mice, Transgenic, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 metabolism, Signal Transduction drug effects, Collagen Type IV genetics, Collagen Type IV metabolism, Endoplasmic Reticulum Stress drug effects, Mutation, Nephritis, Hereditary genetics, Nephritis, Hereditary drug therapy, Nephritis, Hereditary pathology, p38 Mitogen-Activated Protein Kinases metabolism, Taurochenodeoxycholic Acid pharmacology, Taurochenodeoxycholic Acid therapeutic use
- Abstract
COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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