Date of Award

2014

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biology

First Advisor

Ongeri, Elimelda Moige Dr.

Abstract

Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD), and is associated with high morbidity and mortality rates. Key histological changes observed in DN include accumulation of extracellular matrix (ECM) proteins and tubulointerstitial fibrosis. Meprins are metalloproteinases that are abundantly expressed in the brush border membranes of proximal kidney tubules. Meprins are also expressed in leukocytes (monocytes and macrophages) and podocytes. Meprins cleave/degrade extracellular matrix (ECM) proteins such as collagen IV, collagen VI, fibronectin, laminin, and nidogen-1 in vitro. Meprins have been implicated in the pathology of DN. Sepsis is a complex medical condition, where the entire body undergoes an inflammatory state and the presence of a known or suspected infection leads to severe consequences such as multiple organ failure. Acute renal failure (ARF) is a common complication of sepsis. The objective of this study was to evaluate cecal ligation and puncture (CLP)-induced sepsis in meprin deficient mice with type 1 diabetes as a co-morbidity. Low dose Streptozotocin (STZ) was used to induce type-1 diabetes in wild-type (WT) C57BL/6 mice which express high levels of both meprin A and meprin B, and meprin α knockout mice on a C57BL/6 background, which are deficient in meprin A. Cecal ligation and puncture was performed 4 weeks post STZ injection. Blood was collected pre and post CLP to evaluate blood urea nitrogen (BUN) levels. The mice were sacrificed 18hr post CLP and kidney tissue processed for proteomic analysis. BUN levels were significantly higher in CLP mice and meprin α knockout mice had lower mortality rates in comparison to wild-type mice. The results show that meprin deficiency protected mice from kidney injury associated with CLP, suggesting that meprins play a role in kidney injury following CLP-induced sepsis.

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