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Detection of MicroRNA Expression in the Kidneys of Immunoglobulin A Nephropathic Mice
Published on: July 8, 2020
MicroRNA-146a-deficient mice develop immune complex glomerulonephritis
Lucile Amrouche1,2,3, Sylvaine You4,5, Virginia Sauvaget6
1INSERM, U1151, Paris, France. lucile.amrouche@aphp.fr.
Abstract:
MicroRNAs (miRNAs) play an important role in the kidneys under physiological and pathological conditions, but their role in immune glomerulonephritis is unclear. miR-146a has been identified as a key player in innate immunity and inflammatory responses, and in the kidney, this miRNA is involved in the response of injured tubular cells. We studied the renal and immune phenotypes of miR-146a+/+ and miR-146a-/- mice at 12 months of age, and the results showed that miR-146a-/- mice developed autoimmunity during aging, as demonstrated by circulating antibodies targeting double-stranded DNA and an immune complex-mediated glomerulonephritis associated with a mild renal immune infiltrate. In addition, miR-146a-/- mice showed reduced expression of the transmembrane protein Kim1/Tim1, a key regulator of regulatory B cell (Breg) homeostasis, in the kidney and the immune cells. The numbers of memory B cells and plasmablasts were increased in miR-146a-/- mice compared with the numbers in wild-type mice, whereas Bregs were decreased in number and displayed an altered capacity to produce IL-10. Finally, we showed that miR-146a-/- mice develop an autoimmune syndrome with increasing age, and this syndrome includes immune complex glomerulonephritis, which might be due to altered B cell responses associated with Kim1/Tim1 deficiency. This study unravels a link between miR-146a and Kim1 and identifies miR-146a as a significant player in immune-mediated glomerulonephritis pathogenesis.
Insights
MicroRNA-146a deficiency in mice leads to age-dependent autoimmunity and immune complex glomerulonephritis. This occurs due to altered B cell responses and reduced Kim1/Tim1 expression, highlighting miR-146a's role in kidney immune regulation.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- MicroRNAs (miRNAs) are crucial in kidney function and disease.
- The specific role of miR-146a in immune glomerulonephritis remains largely unknown.
- miR-146a is implicated in innate immunity and kidney tubular cell injury responses.
Purpose of the Study:
- To investigate the role of miR-146a in the development of autoimmune glomerulonephritis.
- To examine the impact of miR-146a deficiency on renal and immune cell phenotypes.
- To elucidate the mechanisms linking miR-146a, B cell homeostasis, and kidney inflammation.
Main Methods:
- Comparative analysis of miR-146a knockout (miR-146a-/-) and wild-type (miR-146a+/+) mice at 12 months of age.
- Assessment of renal and immune phenotypes, including autoantibody production and glomerulonephritis.
- Evaluation of transmembrane protein Kim1/Tim1 expression, B cell subsets (regulatory B cells, memory B cells, plasmablasts), and IL-10 production.
Main Results:
- miR-146a-/- mice developed age-dependent autoimmunity, characterized by anti-dsDNA antibodies and immune complex glomerulonephritis.
- Reduced Kim1/Tim1 expression was observed in the kidneys and immune cells of miR-146a-/- mice.
- An increase in memory B cells and plasmablasts, alongside a decrease in regulatory B cells with impaired IL-10 production, was noted in miR-146a-/- mice.
Conclusions:
- miR-146a deficiency promotes an autoimmune syndrome with immune complex glomerulonephritis in aging mice.
- Altered B cell responses, potentially linked to Kim1/Tim1 deficiency, contribute to glomerulonephritis pathogenesis.
- This study establishes a significant role for miR-146a in the development of immune-mediated glomerulonephritis.
