Abstract
BackgroundMeprin metalloproteases are abundantly expressed in the brush border membranes of kidney proximal tubules and small intestines. Meprins are also expressed in podocytes and leukocytes (monocytes and macrophages). Meprins are implicated in the pathophysiology of diabetic nephropathy (DN) but underlying mechanisms are not fully understood. Single nucleotide polymophisms (SNPs) in the meprin β gene were associated with DKD in human subjects. Furthermore, meprin α and β double deficiency resulted in more severe kidney injury and higher mortality rates in mice with Streptozotocin (STZ)-induced type 1 diabetes. Identification of meprin substrates has provided insights on how meprins could modulate kidney injury. Meprin targets in the kidney include extracellular matrix (ECM) proteins, modulators of inflammation, and proteins involved in the protein kinase A (PKA) and PKC signaling pathways. The current study used a global metabolomics approach to determine how meprin β expression impacts the metabolite milieu in diabetes and DKD.MethodsLow dose STZ was used to induce type 1 diabetes in 8-week old wild-type (WT) and meprin β knockout (βKO) mice. Blood and urine samples were obtained at 4 and 8 weeks post-STZ injection. Assays for albumin, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule − 1 (KIM-1), and cystatin C were used for biochemical assessment of kidney injury. Data for biomarkers of kidney injury utilized two-way ANOVA. Metabolomics data analysis utilized UPLC-QTOF MS and multivariate statistics.ResultsThe number of metabolites with diabetes-associated changes in levels were significantly higher in the WT mice when compared to meprin βKO counterparts. Annotated meprin β expression-associated metabolites with strong variable importance in projection (VIP) scores play roles in lipid metabolism (LysoPC(16:1(9Z)), taurocholic acid), amino acid metabolism (indoxyl sulfate, hippuric acid), and neurotransmitter/stress hormone synthesis (cortisol, 3-methoxy-4-hydroxyphenylethylene glycolsulfate, homovanillic acid sulfate). Metabolites that associated with meprin β deficiency include; 3,5-dihydroxy-3′,4′-dimethoxy-6,7-methylenedioxyflavone 3-glucuronide, pantothenic acid, and indoxyl glucuronide (all decreased in plasma).ConclusionTaken together, the annotated metabolites suggest that meprin β impacts complications of diabetes such as DKD by altering distinct metabolite profiles.
Highlights
Meprin metalloproteases are abundantly expressed in the brush border membranes of kidney proximal tubules and small intestines
Meprin β expression is associated with higher levels of kidney injury Overall, WT mice with STZ-induced type 1 diabetes had higher levels of kidney injury when compared to meprin β knockout (βKO) mice
The differences in indoxyl sulfate level changes in the current study indicate the late onset of kidney injury in meprin βKO mice when compared to WT mice
Summary
Meprin metalloproteases are abundantly expressed in the brush border membranes of kidney proximal tubules and small intestines. Meprin β gene single nucleotide polymorphisms (SNPs) were associated with DN and end stage renal disease (ESRD) in the Pima Indians, a Native American ethnic group with extremely high incidences of type 2 diabetes and ESRD [9] Both meprin α and meprin β gene and protein expression levels were down-regulated in the kidneys of diabetic rats, and db/db mice before development of overt kidney disease. The objective of the current study was to use meprin β knockout mice (in which the meprin β gene is disrupted) and global metabolomics analysis to gain understanding of the mechanisms by which meprin β modulate kidney injury by identifying meprin β-associated changes in plasma and urine metabolites
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