Meprin β deficiency associated with higher levels of neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule (KIM-1) in mice with streptozotocin induced type 1 diabetes

Abstract

Diabetic nephropathy (DN) is the leading cause of end stage renal disease, and is associated with high morbidity and mortality rates. The pathophysiology of DN includes both glomerular and tubulointerstitial damage. Meprins are metalloproteinases which are most abundantly expressed in the brush border membranes of proximal kidney tubules. Meprins are also expressed in leukocytes (monocytes and macrophages) and podocytes. Meprins have been implicated in the pathology of acute and chronic kidney injury. Single nucleotide polymorphisms (SNPs) in the meprin β gene were associated in human DN in the Pima Indians, suggesting a role for meprins in the pathophysiology of DN. The current study was done to determine the mechanisms by which meprins modulate the progression of DN in mice. Low dose streptozotocin (STZ) was used to induce type 1 diabetes in 8 week old male wild-type (WT) and meprin β knockout mice (βKO) on a C57BL/6 background. Control mice were injected with sodium citrate buffer. Urine and blood samples were collected at 4 and 8 weeks post STZ injection. The mice were sacrificed at 8 weeks post-STZ injection and kidney tissue harvested for analysis using metabolomics and proteomic approaches. Enzyme-linked immunosorbent assays (ELISA) were used to determine the levels of two tubular kidney injury markers, neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1). When compared to non-diabetic controls, meprin β KO mice with STZ-induced type 1 diabetes had significantly higher levels of plasma NGAL at 4 weeks but not at 8 weeks post STZ injection. The levels of urinary KIM-1 were significantly higher in meprin βKO mice at both 4 weeks and 8 weeks when compared to their wild-type counterparts. Taken together, the data suggest that presence of meprin β partially protects mice from the tubular kidney injury associated with diabetes. This is in contrast to outcomes in ischemia/reperfusion induced acute kidney injury where meprin deficiency was previously shown to be protective. Further analysis will determine the kidney meprin targets and metabolic pathways which play a role in the progression of DN.