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Transcriptome Analysis of BAFF/BAFF-R System in Murine Nephrotoxic Serum Nephritis
Tamara Möckel1, Sebastian Boegel1, Andreas Schwarting1,2
1Division of Rheumatology and Clinical Immunology, Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany.
Abstract:
Chronic kidney disease (CKD) is an emerging cause for morbidity and mortality worldwide. Acute kidney injury (AKI) can transition to CKD and finally to end-stage renal disease (ESRD). Targeted treatment is still unavailable. NF-κB signaling is associated with CKD and activated by B cell activating factor (BAFF) via BAFF-R binding. In turn, renal tubular epithelial cells (TECs) are critical for the progression of fibrosis and producing BAFF. Therefore, the direct involvement of the BAFF/BAFF-R system to the pathogenesis of CKD is conceivable. We performed non-accelerated nephrotoxic serum nephritis (NTN) as the CKD model in BAFF KO (B6.129S2-Tnfsf13b/J), BAFF-R KO (B6(Cg)-Tnfrsf13c/J) and wildtype (C57BL/6J) mice to analyze the BAFF/BAFF-R system in anti-glomerular basement membrane (GBM) disease using high throughput RNA sequencing. We found that BAFF signaling is directly involved in the upregulation of collagen III as BAFF ko mice showed a reduced expression. However, these effects were not mediated via BAFF-R. We identified several upregulated genes that could explain the effects of BAFF in chronic kidney injury such as Txnip, Gpx3, Igfbp7, Ccn2, Kap, Umod and Ren1. Thus, we conclude that targeted treatment with anti-BAFF drugs such as belimumab may reduce chronic kidney damage. Furthermore, upregulated genes may be useful prognostic CKD biomarkers.
Insights
B cell activating factor (BAFF) signaling contributes to chronic kidney disease (CKD) progression by upregulating collagen III. Targeting BAFF may offer a new therapeutic strategy for CKD patients.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Chronic kidney disease (CKD) is a growing global health concern with limited targeted treatments.
- The NF-κB signaling pathway, activated by B cell activating factor (BAFF), is implicated in CKD.
- Renal tubular epithelial cells (TECs) produce BAFF and are crucial in kidney fibrosis.
Purpose of the Study:
- To investigate the role of the BAFF/BAFF-R system in the pathogenesis of anti-glomerular basement membrane (GBM) disease, a model for CKD.
- To analyze the impact of BAFF and BAFF-receptor (BAFF-R) deficiency on CKD development using high-throughput RNA sequencing.
Main Methods:
- Non-accelerated nephrotoxic serum nephritis (NTN) model in BAFF knockout (KO), BAFF-R KO, and wildtype mice.
- High-throughput RNA sequencing to analyze gene expression changes in the kidneys.
- Analysis of BAFF signaling in the context of anti-GBM disease.
Main Results:
- BAFF signaling directly contributes to the upregulation of collagen III in CKD, as evidenced by reduced expression in BAFF KO mice.
- The observed effects of BAFF on collagen III were not mediated through the BAFF-R.
- Several genes, including Txnip, Gpx3, Igfbp7, Ccn2, Kap, Umod, and Ren1, were identified as upregulated and potentially involved in BAFF's role in CKD.
Conclusions:
- The BAFF/BAFF-R system is involved in the pathogenesis of CKD, particularly in collagen III upregulation.
- Targeted inhibition of BAFF, for example, with belimumab, may represent a therapeutic approach to mitigate chronic kidney damage.
- The identified upregulated genes may serve as valuable prognostic biomarkers for CKD.
