ADAM17 Deletion Protects Against Type1 Diabetes-Associated Kidney Injury by Modulating Inflammatory and Fibrotic Pathways

Riera, M.; Martyn, C.; Pujol-Brugues, J.; Marquez, E.; Rodriguez, E.; Palau, V.; Soler, M. J.; Castaneda, J. S. S.; Pilco, M.; del Risco, J.; Crespo, M.; Barrios, C.

doi:10.64898/2026.02.05.704041

bioRxiv · 10.64898/2026.02.05.704041

ADAM17 Deletion Protects Against Type1 Diabetes-Associated Kidney Injury by Modulating Inflammatory and Fibrotic Pathways

Riera, M.·Martyn, C.·Pujol-Brugues, J.·Marquez, E.·Rodriguez, E.·Palau, V.·Soler, M. J.·Castaneda, J. S. S.·Pilco, M.·del Risco, J.·Crespo, M.·Barrios, C.

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Abstract

0BackgroundA Disintegrin and Metalloprotease 17 (ADAM17) is a key sheddase regulating multiple inflammatory and growth factor-related pathways implicated in diabetic kidney disease (DKD). While cell-specific deletion of ADAM17 has shown renoprotective effects, the impact of global ADAM17 ablation in the context of diabetes remains incompletely understood. MethodsWe investigated the effects of tamoxifen-induced global Adam17 deletion in a murine model of type 1 diabetes induced by streptozotocin. Renal function, structural injury, inflammatory responses, stress-related signalling pathways, and fibrotic remodelling were comprehensively assessed and compared between diabetic Adam17 knockout and control mice. ResultsDespite persistent hyperglycaemia and albuminuria, diabetic Adam17 knockout mice exhibited preservation of glomerular filtration rate and marked attenuation of diabetes-associated renal injury. Global Adam17 deletion reduced mesangial expansion and structural damage, limited macrophage infiltration and chemokine expression, and significantly attenuated fibrotic remodelling. At the molecular level, Adam17 deficiency was associated with selective modulation of stress-related signalling pathways, including reduced activation of the PI3K/Akt axis and partial preservation of mitochondrial stress regulators, without evidence of a generalized suppression of cellular stress responses. ConclusionsOur findings demonstrate that global deletion of ADAM17 confers robust protection against diabetes-induced kidney injury through coordinated attenuation of inflammatory activation, stress-related signalling, and fibrotic progression. These results highlight the context-dependent role of ADAM17 in diabetic kidney disease and support the concept that therapeutic strategies targeting ADAM17-related pathways may require tissue- and disease-specific modulation to achieve renoprotective effects.

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Riera, M., Martyn, C., Pujol-Brugues, J., Marquez, E., Rodriguez, E., Palau, V., Soler, M. J., Castaneda, J. S. S., Pilco, M., del Risco, J., Crespo, M., Barrios, C.. 2026-02-08. ADAM17 Deletion Protects Against Type1 Diabetes-Associated Kidney Injury by Modulating Inflammatory and Fibrotic Pathways. https://doi.org/10.64898/2026.02.05.704041

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