Meprins are multidomain zinc metalloproteases that are highly expressed in mammalian kidney and intestinal brush border membranes and in leukocytes and certain cancer cells. Mature meprins are oligomers of evolutionarily related, separately encoded ␣ and/or  subunits. Homooligomers of meprin ␣ are secreted; oligomers containing meprin  are plasma membrane associated. Meprin substrates include bioactive peptides and extracellular matrix proteins. Meprins have been implicated in cancer and intestinal inflammation. Additionally, meprin  is a candidate gene for diabetic nephropathy. To elucidate in vivo functions of these metalloproteases, meprin  null mice were generated by targeted disruption of the meprin  gene on mouse chromosome 18q12. Analyses of meprin  knockout mice indicated that (i) 50% fewer null mice are born than the Mendelian distribution predicts, (ii) null mice that survive develop normally and are viable and fertile, (iii) meprin  knockout mice lack membrane-associated meprin ␣ in kidney and intestine, and (iv) null mice have changes in renal gene expression profiles compared to wild-type mice as assessed by microarray analyses. Thus, disruption of the meprin  allele in mice affects embryonic viability, birth weight, renal gene expression profiles, and the distribution of meprin ␣ in kidney and intestine.Meprins (meprin A [EC 3.4.24.18] and meprin B [EC 3.4.24.63]), metalloproteases of the astacin family, comprise approximately 5% of kidney brush border membrane protein in mice (2, 3). They are also expressed in intestinal brush border membranes, in leukocytes, and in certain epithelial cancer cells (17,21). Various growth factors, cytokines, and extracellular matrix proteins are substrates for meprin in vitro; among the best substrates are gastrin, gastrin-releasing peptide, monocyte chemoattractant protein-1, osteopontin, and laminin (1, 15). The nature of these substrates and the expression patterns of the subunits in acute renal failure, intestinal disease, and cancerous cells implicate meprins in the regulation of growth, inflammation, cancer cell metastasis, and matrix remodeling (5,15,17,18,21,33).The meprin subunits, ␣ and , associate to form homo-or heterooligomers (19). Although the subunits are encoded by distinct genes on different chromosomes (Mep1␣ on chromosome 6 in humans and 17 in mice and Mep1 on chromosome 18 in both species), under some circumstances there is coordinate regulation of the expression of the genes that results in heterooligomeric protein complexes (4). Meprin ␣ and  subunits are 42% identical at the amino acid level and share the same domain structure, except that meprin ␣ contains an inserted (I) domain which is not present in meprin  (20). The I domain directs the proteolytic cleavage of meprin ␣ during maturation in the endoplasmic reticulum so that the bulk of the subunit is released from the membrane. The consequence of the cleavage is that meprin ␣ is secreted unless it interacts with membrane-associated meprin . In vivo, meprin ␣ is secreted as ...