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Meprin Metalloprotease Deficiency Associated with Higher Mortality Rates and More Severe Diabetic Kidney Injury in
John E Bylander1, Faihaa Ahmed2, Sabena M Conley2
1Department of Environmental Sciences, Pennsylvania State University, Harrisburg, Middletown, PA 17057, USA.
Abstract:
Meprins are membrane-bound and secreted metalloproteinases consisting of α and/or β subunits that are highly expressed in kidney epithelial cells and are differentially expressed in podocytes and leukocytes (macrophages and monocytes). Several studies have implicated meprins in the progression of diabetic nephropathy (DN) and fibrosis-associated kidney disease. However, the mechanisms by which meprins modulate DN are not understood. To delineate the role of meprins in DN, we subjected meprin αβ knockout (αβKO) mice and their wild-type (WT) counterparts to streptozotocin-induced type 1 diabetes. The 18-week survival rates were significantly lower for diabetic meprin αβKO mice when compared to those for their WT counterparts. There were significant decreases in mRNA and protein levels for both meprin α and β in diabetic WT kidneys. Furthermore, the blood urea nitrogen levels and urine albumin/creatinine ratios increased in diabetic meprin αβKO but not in diabetic WT mice, indicating that meprins may be protective against diabetic kidney injury. The brush border membrane levels of villin, a meprin target, significantly decreased in diabetic WT but not in diabetic meprin αβKO kidneys. In contrast, isoform-specific increases in cytosolic levels of the catalytic subunit of PKA, another meprin target, were demonstrated for both WT and meprin αβKO kidneys.
Insights
Meprins protect against diabetic kidney injury. In a mouse model of diabetes, meprin knockout mice showed reduced survival and worsened kidney damage compared to wild-type mice.
Area of Science:
- Biochemistry
- Nephrology
- Molecular Biology
Background:
- Meprins are metalloproteinases found in kidney epithelial cells.
- Meprins are implicated in diabetic nephropathy (DN) and kidney fibrosis.
- The precise role of meprins in DN pathogenesis remains unclear.
Purpose of the Study:
- To investigate the role of meprins in diabetic kidney injury.
- To determine if meprins are protective or detrimental in the context of diabetes.
Main Methods:
- Streptozotocin-induced type 1 diabetes model in meprin αβ knockout (αβKO) and wild-type (WT) mice.
- Assessment of survival rates, kidney function markers (blood urea nitrogen, urine albumin/creatinine ratio), and meprin target protein levels (villin, PKA).
Main Results:
- Diabetic αβKO mice exhibited significantly lower survival rates compared to diabetic WT mice.
- Diabetic αβKO mice showed increased blood urea nitrogen and albuminuria, indicating kidney damage.
- Meprin α and β expression decreased in diabetic WT kidneys.
- Villin levels decreased in diabetic WT kidneys, but not in αβKO kidneys, suggesting meprin activity on villin.
Conclusions:
- Meprins appear to be protective against diabetic kidney injury.
- Loss of meprins exacerbates kidney damage in a model of type 1 diabetes.
- Further research is needed to elucidate the specific mechanisms by which meprins modulate DN.
