Abstract
Meprin metalloproteinases have been shown to play a role in the progression of diabetic nephropathy (DN) in both mice and humans. However, the mechanisms involved are not fully understood. The objective of this study was to determine whether PKC, a serine/threonine kinase known to play a role in DN, is a meprin substrate. Activated forms of purified recombinant meprin A and B were incubated for 0‐4 h with cytosolic‐enriched proteins from meprin αβ double knockout mouse kidneys (which lack endogenous meprins) and protein lysates extracted from Mardin‐Darby canine kidney (MDCK) cells (which do not express meprins). The levels of PKCα were determined by Western blot analysis using anti‐PKCα specific antibodies coupled with optic densitometry. Incubation with meprin B significantly reduced the levels of PKCα present in the kidney proteins and MDCK lysates. This decrease was not observed in proteins incubated with meprin A or control reactions without meprins, suggesting isoform‐specific degradation of PKCα. To confirm the degradation, human PKCα proteins were expressed in yeast, purified by GST‐affinity chromatography, and incubated with the activated meprins. These data suggest that meprin B may impact kidney function via proteolysis of PKCα. Consistently, PKC isoforms are upregulated in DN and PKCα has been shown to play a role in the development of albuminuria in mice with streptozotocin‐induced type 1 diabetes.Grant Funding Source: Supported by NIGMS (SC3GM102049)
Published Version
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