The genetic deletion of the Dual Specificity Phosphatase 3 (DUSP3) attenuates kidney damage and inflammation following ischaemia/reperfusion injury in mouse

Abstract

Aim: Dual Specificity Phosphatase 3 (DUSP3) regulates the innate immune response, with a putative role in angiogenesis. Modulating inflammation and perfusion contributes to renal conditioning against ischaemia/reperfusion (I/R). We postulate that the functional loss of DUSP3 is associated with kidney resistance to I/R. Methods: Ten C57BL/6 male WT and Dusp3 −/− mice underwent right nephrectomy and left renal I/R (30 min/48 hours). Renal injury was assessed based on serum levels of urea (BUN) and Jablonski score. The expression of CD31 and VEGF vascular markers was quantified by RT-qPCR and immuno-staining. Renal resistivity index (RRI) was measured in vivo by Doppler ultrasound. Comparative phosphoproteomics was conducted using IMAC enrichment of phosphopeptides. Inflammatory markers were quantified at both mRNA and protein levels in ischaemic vs non-ischaemic kidneys in WT vs Dusp3 −/− . Results: At baseline, we located DUSP3 in renal glomeruli and endothelial cells. CD31-positive vascular network was significantly larger in Dusp3 −/− kidneys compared to WT, with a lower RRI in Dusp3 −/− mice. Following I/R, BUN and Jablonski score were significantly lower in Dusp3 −/− vs WT mice. Phosphoproteomics highlighted a down-regulation of inflammatory pathways and up-regulation of phospho-sites involved in cell metabolism and VEGF-related See editorial article: Ivy J.R. 2022 Does renal ischaemia/reperfusion injury bite the DUSP3? Acta Physiol (Oxf). e13763.

Recent advances in kidney research

“…This approach has the potential to unravel unknown signaling mechanisms. It was found that following I/R, serum levels of urea were significantly lower in Dusp3 −/− versus wild‐type mice 3 . The authors conclude that Genetic inactivation of Dusp3 is associated with kidney conditioning against ischemia reperfusion that is possibly due to attenuated inflammation and improved perfusion 3 …”

“…It was found that following I/R, serum levels of urea were significantly lower in Dusp3 −/− versus wild-type mice. 3 The authors conclude that Genetic inactivation of Dusp3 is associated with kidney conditioning against ischemia reperfusion that is possibly due to attenuated inflammation and improved perfusion. 3 When one does experimental research with fundamental questions, it is sometimes not easy for the researchers to see the bridge to therapeutic or diagnostic applications.…”

“…3 The authors conclude that Genetic inactivation of Dusp3 is associated with kidney conditioning against ischemia reperfusion that is possibly due to attenuated inflammation and improved perfusion. 3 When one does experimental research with fundamental questions, it is sometimes not easy for the researchers to see the bridge to therapeutic or diagnostic applications. This can then also lead to social discussions about the importance of basic research.…”

“…Finding pathways that are involved in kidney damage or protection are of high interest to kidney physiology. In this context a work by Khbouz et al investigated the role of the Dual Specificity Phosphatase 3 (DUSP3) that regulates the innate immune response, with a putative role in angiogenesis 3 . From this rather imprecise functional attribution, DUSP3 seems an interesting object of investigation in an ischemia reperfusion (I/R) model.…”

“…In this context a work by Khbouz et al investigated the role of the Dual Specificity Phosphatase 3 (DUSP3) that regulates the innate immune response, with a putative role in angiogenesis. 3 From this rather imprecise functional attribution, DUSP3 seems an interesting object of investigation in an ischemia reperfusion (I/R) model. This was certainly one motivation to investigate a DUSP3 knockout mice model.…”