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TGF-β upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-α heterozygous mice
- Source :
- American Journal of Physiology-Renal Physiology. 296:F512-F520
- Publication Year :
- 2009
- Publisher :
- American Physiological Society, 2009.
-
Abstract
- Calcineurin is an important intracellular signaling molecule which can be inhibited by cyclosporin resulting in immune suppression and nephrotoxicity. Previously, we reported that homozygous loss of the α isoform of calcineurin impairs kidney development and function and mimics many features of cyclosporin nephrotoxicity. However, early lethality of null mice prevented further study of renal changes. Alternatively, we examined aged heterozygous (CnAα+/−) mice. In addition to renal dysfunction and inflammation, we find that CnAα+/− mice spontaneously develop tertiary lymphoid aggregates in the kidney, small intestine, liver, and lung. Lymphoid aggregates contain both T cells and B cells and exhibited organization suggestive of tertiary lymphoid organs (TLOs). Kidney function and TLO formation were highly correlated suggesting that this process may contribute to nephrotoxicity. Consistent with previous findings, transforming growth factor (TGF)-β is significantly increased in CnAα+/− mice. Neutralization of TGF-β attenuated TLO formation and improved kidney function. In conclusion, we report that haploinsufficiency of CnAα causes uregulation of TGF-β which contributes to chronic inflammation and formation of TLOs. While the process that leads to TLOs formation in transplant allografts is unknown, TLOs are associated with poor clinical prognosis. This study suggests that calcineurin inhibition itself may lead to TLO formation and that TGF-β may be a novel therapeutic target.
- Subjects :
- Aging
Heterozygote
medicine.medical_specialty
Lymphoid Tissue
Physiology
Biology
Kidney
Nephrotoxicity
Mice
Immune system
Downregulation and upregulation
Transforming Growth Factor beta
Internal medicine
medicine
Animals
Protein Isoforms
Mice, Knockout
Calcineurin
Heterozygote advantage
Articles
Up-Regulation
medicine.anatomical_structure
Endocrinology
Kidney Diseases
Intracellular
Transforming growth factor
Subjects
Details
- ISSN :
- 15221466 and 1931857X
- Volume :
- 296
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Renal Physiology
- Accession number :
- edsair.doi.dedup.....c1d52e75446c42e0ea2341afcf2cba23