Specific calpain inhibition protects kidney against inflammaging

• Published in: Scientific reports Vol. 7; no. 1; pp. 8016 - 16
• Main Authors: Hanouna, Guillaume, Mesnard, Laurent, Vandermeersch, Sophie, Perez, Joëlle, Placier, Sandrine, Haymann, Jean-Philippe, Campagne, Fabien, Moroch, Julien, Bataille, Aurélien, Baud, Laurent, Letavernier, Emmanuel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.08.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 631/443/272; 64; 64/60; 692/4022/272; Aging; Aging - drug effects; Angiotensin; Angiotensin II; Animal models; Animals; Arteries; Arteries - drug effects; Arteries - growth & development; Biochemistry, Molecular Biology; Calcium-Binding Proteins - pharmacology; Calcium-Binding Proteins - therapeutic use; Calpain; Calpain - antagonists & inhibitors; Calpain - metabolism; Calpastatin; Cell activation; Cells, Cultured; Cysteine Proteinase Inhibitors - pharmacology; Cysteine Proteinase Inhibitors - therapeutic use; Cytokines - metabolism; Human health and pathology; Humanities and Social Sciences; IL-1β; Inflammasomes; Inflammasomes - metabolism; Inflammation; Kidney - drug effects; Kidney - growth & development; Kidneys; Life Sciences; Life span; Macrophages; Metastases; Mice; Mice, Inbred C57BL; multidisciplinary; NF-kappa B - metabolism; NF-κB protein; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Peritonitis; Peritonitis - drug therapy; Rabbits; Ribonucleic acid; RNA; Rodents; Science; Science (multidisciplinary); Senescence; Spleen; Transgenic mice; Tumors; Uric acid; Urology and Nephrology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-07922-1

Calpains are ubiquitous pro-inflammatory proteases, whose activity is controlled by calpastatin, their specific inhibitor. Transgenic mice over-expressing rabbit calpastatin (CalpTG) are protected against vascular remodelling and angiotensin II-dependent inflammation. We hypothesized that specific calpain inhibition would protect against aging-related lesions in arteries and kidneys. We analysed tissues from 2-months and 2-years-old CalpTG and wild-type mice and performed high throughput RNA-Sequencing of kidney tissue in aged mice. In addition, we analysed inflammatory response in the kidney of aged CalpTG and wild-type mice, and in both in vivo (monosodium urate peritonitis) and in vitro models of inflammation. At two years, CalpTG mice had preserved kidney tissue, less vascular remodelling and less markers of senescence than wild-type mice. Nevertheless, CalpTG mice lifespan was not extended, due to the development of lethal spleen tumors. Inflammatory pathways were less expressed in aged CalpTG mice, especially cytokines related to NF-κB and NLRP3 inflammasome activation. CalpTG mice had reduced macrophage infiltration with aging and CalpTG mice produced less IL-1α and IL-1β in vivo in response to inflammasome activators. In vitro , macrophages from CalpTG mice produced less IL-1α in response to particulate activators of inflammasome. Calpains inhibition protects against inflammaging, limiting kidney and vascular lesions related to aging.