Genetic Variants of TNFAIP3 May Protect the Kidneys from Damage

A breakthrough in gene variants of an inflammation “brake” brings researchers one step closer to developing personalized treatments for those at risk of kidney disease and kidney failure.

Genetic Variants of TNFAIP3 May Protect the Kidneys from Damage

Paradoxically, a gene variant that increases inflammation also has a protective effect on the kidneys. Seen here, kidney cell nuclei (blue) and an influx of immune regulatory cells (pink) that prevent damage in an injured kidney. Image Credit: Garvan Institute of Medical Research.

The Garvan Institute of Medical Research, University of New South Wales, Sydney, and Westmead Hospital researchers discovered that common genetic variants of TNFAIP3, which enhance inflammation in the body, can paradoxically safeguard the kidneys from impairment in the short term.

We wanted to investigate whether inherited differences in how people regulate inflammation could lead to better or worse kidney health outcomes. We focused on the TNFAIP3 gene, which produces a protein called A20 that acts as a ‘brake’ on inflammation. Common variants of TNFAIP3 have been linked to autoimmune disease, but their role in kidney disease was unknown. Our discovery that some genetic variants can be protective against inflammation could lead to a simple genetic test that helps predict the risk of kidney disease for patients.”

Shane Grey, Study Senior Author, Professor, and Head, Transplant Immunology Lab, Garvan Institute of Medical Research

Unexpected Protective Effect of Pro-Inflammatory Variant

Acute kidney injury, described as a fast and rapid reduction in kidney function caused in part by inflammation, is a major risk factor for the progression of chronic kidney disease, which affects around one in every 10 Australians. There are currently few treatment options for acute kidney injury, as well as imprecise techniques for predicting who is most at risk of poor recovery or kidney failure.

The researchers initially looked into how different TNFAIP3 variants affect A20 function, discovering a number of unusual variants that diminish A20’s anti-inflammatory activity. They then used a mouse model to examine the impact of one of the variants that enhances inflammation following kidney injury.

Despite increasing inflammation, this rare variant surprisingly protected the kidneys from injury. We found this protection to be due to another of A20’s functions: preventing cells from self-destructing. Our study indicates that these ‘hot’ TNFAIP3 variants can alter the outcome of kidney injury, and they do so through complex effects on inflammation and cell survival.”

Natasha Rogers, Professor, Nephrologist and Head, Transplantation Westmead Hospital

Natasha Rogers co-led the research.

The observations were published in the journal Kidney International.

New Treatment Approaches on the Horizon

More work is needed, but these findings bring us closer to being able to predict who is at risk of poor kidney recovery, and open personalized treatment approaches,” explains Professor Grey.

The research could lead to the development of a simple genetic test that would allow doctors to assess whether a person carries a “hot” version of the inflammation control gene, providing families with greater assurance about their risk factors.

By gaining a better understanding of how variants of the TNFAIP3 gene influence kidney health, this research brings us closer to precision diagnostics and tailored treatments for acute kidney injury. Rather than a one-size-fits-all approach, we may be able to determine the best way to monitor a patient’s condition based on their variant of TNFAIP3, and personalize interventions to boost their kidney recovery and long-term health.”

Shane Grey, Study Senior Author, Professor, and Head, Transplant Immunology Lab, Garvan Institute of Medical Research

Source:
Journal reference:

Rogers, N. M., et al. (2023) The impact of the cytoplasmic ubiquitin ligase TNFAIP3 gene variation on transcription factor NF-κB activation in acute kidney injury. Kidney International. doi.org/10.1016/j.kint.2023.02.030.

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