Meprins cleave the catalytic subunit of protein kinase A in a meprin isoform‐specific manner

Abstract

Meprins are metalloproteases that are abundantly expressed in the brush border membrane of proximal kidney tubules and small intestines. Meprins are also expressed in podocytes, skin, and leukocytes. Meprins are redistributed to the cytosol after kidney ischemia/reperfusion, and have been implicated in the pathology of diabetic nephropathy (DN). There is increasing knowledge of in vivo kidney meprin substrates, and recently villin and actin were found to be cleaved by meprins. The objective of this study was to determine whether meprins cleave the catalytic subunit of protein kinase A (PKAcat), and whether the levels of PKAcat are changed in DN. Kidney proteins from meprin αβ double knockout (KO) mice, and purified recombinant human PKAcat were incubated with activated forms of either homomeric meprin A (α‐α) or meprin B (β‐β). The proteins were resolved by SDS‐PAGE and probed by Western blot analysis using PKAcat specific antibodies. Only the meprin B isoform cleaved PKAcat. Cytosolic levels of PKAcat were elevated in kidneys from both WT and meprin KO mice with streptozotocin‐induced type 1 diabetes. Cytosolic PKAcat leveles were higher in WT diabetic kidneys than in meprin double KO diabetic kidneys. The PKA signaling pathway plays a role in glomerular extracellular matrix (ECM) metabolism. Accumulation of ECM proteins is a hallmark of DN, and meprins could modulate the pathology of DN via cleavage of PKAcat.