The renal inflammatory network of nephronophthisis

Abstract Renal ciliopathies are the leading cause of inherited kidney failure. In autosomal dominant polycystic kidney disease (ADPKD), mutations in the ciliary gene PKD1 lead to the induction of CCL2, which promotes macrophage infiltration in the kidney. Whether or not mutations in genes involved i...

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Bibliographic Details
Published in:Human molecular genetics 2022-07, Vol.31 (13), p.2121-2136
Main Authors: Quatredeniers, Marceau, Bienaimé, Frank, Ferri, Giulia, Isnard, Pierre, Porée, Esther, Billot, Katy, Birgy, Eléonore, Mazloum, Manal, Ceccarelli, Salomé, Silbermann, Flora, Braeg, Simone, Nguyen-Khoa, Thao, Salomon, Rémi, Gubler, Marie-Claire, Kuehn, E Wolfgang, Saunier, Sophie, Viau, Amandine
Format: Article
Language:English
Subjects:
Adaptive immunology
Genetics
Human genetics
Human health and pathology
Immunology
Innate immunity
Life Sciences
Urology and Nephrology
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Summary:Abstract Renal ciliopathies are the leading cause of inherited kidney failure. In autosomal dominant polycystic kidney disease (ADPKD), mutations in the ciliary gene PKD1 lead to the induction of CCL2, which promotes macrophage infiltration in the kidney. Whether or not mutations in genes involved in other renal ciliopathies also lead to immune cells recruitment is controversial. Through the parallel analysis of patients’ derived material and murine models, we investigated the inflammatory components of nephronophthisis (NPH), a rare renal ciliopathy affecting children and adults. Our results show that NPH mutations lead to kidney infiltration by neutrophils, macrophages and T cells. Contrary to ADPKD, this immune cell recruitment does not rely on the induction of CCL2 in mutated cells, which is dispensable for disease progression. Through an unbiased approach, we identified a set of inflammatory cytokines that are upregulated precociously and independently of CCL2 in murine models of NPH. The majority of these transcripts is also upregulated in NPH patient renal cells at a level exceeding those found in common non-immune chronic kidney diseases. This study reveals that inflammation is a central aspect in NPH and delineates a specific set of inflammatory mediators that likely regulates immune cell recruitment in response to NPH genes mutations.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddac014