Meprin-β activity modulates the β-catalytic subunit of protein kinase A in ischemia-reperfusion-induced acute kidney injury.

Meprin metalloproteases have been implicated in the progression of kidney injury. Previous work from our group has shown that meprins proteolytically process the catalytic subunit of protein kinase A resulting in decreased kinase activity. The goal of the present study was to determine the duanyu1529-C isoforms impacted by meprin-β and whether meprin-β expression affects downstream mediators of the signaling pathway in ischemia-reperfusion (IR)-induced kidney injury. IR was induced in 12-wk-old male wild-type (WT) and meprin-β knockout (βKO) mice. Madin-Darby canine kidney cells transfected with meprin-β cDNA were also subjected to 2 h of hypoxia. Western blot analysis was used to evaluate levels of total phosphorylated and p-ERK1/2. Meprin-β expression enhanced kidney injury as indicated by levels of neutrophil gelatinase-associated lipocalin and cystatin C. IR-associated decreases were observed in levels of in kidney tissue from WT mice but not βKO mice, suggesting that meprin-β expression/activity is responsible for the in vivo reduction in kinase activity. Significant increases in levels of were observed in kidney lysates for WT mice but not βKO mice at 6 h post-IR. Proximal tubule duanyu1529-Cβ increases in WT but not βKO kidneys were demonstrated by fluorescent microscopy. Furthermore, IR-induced injury was associated with significant increases in p-ERK levels for both genotypes. The present data demonstrate that meprin-β enhances IR-induced kidney injury in part by modulating mediators of the duanyu1529-Cβ signaling pathway.

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