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Meprin Interactions with the Catalytic Subunit of Protein Kinase A in Ischemia Reperfusion‐induced Renal Injury

Meprins are metalloptroteasses that are abundantly expressed in the brush border membranes (BBM) of proximal kidney tubules. Disruption of the meprin genes and pre‐treatment with meprin inhibitors both protect mice from ischemia reperfusion (IR)‐induced renal injury. In IR, meprins redistribute from the BBM to the cytosol and basolateral membranes, bringing them into contact with proteins in these cell compartments. We recently showed that meprins are capable of cleaving the catalytic subunit of protein kinase A (PKA C) in an isoform specific manner. The objective of the current study was to determine whether this interaction is significant in IR‐induced renal injury. To this end, IR‐renal injury was induced in 12 week old male wild‐type (WT) and meprin αβ double knockout (KO) mice on a C57BL/6 background. The mice were sacrificed at 3h post‐IR. Blood urea nitrogen (BUN) was assayed as an indicator of kidney injury. Kidney tissues were fixed in Carnoy's fixative, paraffin embedded, and 5 µM sections cut onto slides for immunohistochemical analysis. Confocal microscopy was used to evaluate the localization of meprins and PKA C in the kidney tissue. In WT mice, at 3h post IR, the levels of PKA C were significantly higher in the distal tubules (which lack meprins) when compared to the meprin expressing proximal tubules. This change was not observed in sham operated control WT mice or in meprin αβ KO mice (which lack endogenous meprins) subjected to IR. As expected, meprins redistributed from the BBM to the cytosolic compartments of proximal tubule cells, where PKA C is found. Taken together, the data suggest that meprins could modulate the response to IR‐induced acute kidney injury via interaction with the PKA signaling pathway.