| First Author | Ahmed F | Year | 2020 |
| Journal | Am J Physiol Renal Physiol | Volume | 318 |
| Issue | 5 | Pages | F1147-F1159 |
| PubMed ID | 32174142 | Mgi Jnum | J:294817 |
| Mgi Id | MGI:6451391 | Doi | 10.1152/ajprenal.00571.2019 |
| Citation | Ahmed F, et al. (2020) Meprin-beta activity modulates the beta-catalytic subunit of protein kinase A in ischemia-reperfusion-induced acute kidney injury. Am J Physiol Renal Physiol 318(5):F1147-F1159 |
| abstractText | 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 (PKA-C), resulting in decreased PKA-C kinase activity. The goal of the present study was to determine the PKA-C isoforms impacted by meprin-beta and whether meprin-beta expression affects downstream mediators of the PKA signaling pathway in ischemia-reperfusion (IR)-induced kidney injury. IR was induced in 12-wk-old male wild-type (WT) and meprin-beta knockout (betaKO) mice. Madin-Darby canine kidney cells transfected with meprin-beta cDNA were also subjected to 2 h of hypoxia. Western blot analysis was used to evaluate levels of total PKA-C, PKA-Calpha, PKA-Cbeta, phosphorylated (p-)PKA-C, and p-ERK1/2. Meprin-beta expression enhanced kidney injury as indicated by levels of neutrophil gelatinase-associated lipocalin and cystatin C. IR-associated decreases were observed in levels of p-PKA-C in kidney tissue from WT mice but not betaKO mice, suggesting that meprin-beta expression/activity is responsible for the in vivo reduction in kinase activity. Significant increases in levels of PKA-Cbeta were observed in kidney lysates for WT mice but not betaKO mice at 6 h post-IR. Proximal tubule PKA-Cbeta increases in WT but not betaKO 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-beta enhances IR-induced kidney injury in part by modulating mediators of the PKA-Cbeta signaling pathway. |
