William H. Baricos

Mechanisms of Disease

	Professor of Biochemistry Ph.D. (Tulane, 1972)
	Phone: (504) 588-5292
	FAX: (504) 584-2739
	Address: 1430 Tulane Ave., Box SL-43 New Orleans LA 70112
	Email: baricosw@tulane.edu

Research Interests

Accumulation of glomerular extracellular matrix (ECM) is a pivotal event in diabetic nephropathy. The mechanisms responsible for this accumulation are unknown and no doubt complex and diverse. However, ECM accumulation must ultimately result from increased synthesis, decreased degradation, or both. Recent studies from this lab using mesangial cells cultured on thin films of 125I-ECM, have demonstrated that ECM degradation by cultured rat and human mesangial cells is mediated by a plasminogen activator (PA)/plasmin/gelatinase cascade. This cascade is initiated by tissue plasminogen activator (tPA) and results in the production of plasmin and active gelatinase, proteinases that then degrade the ECM.

Our overall hypothesis is that in diabetic nephropathy, glomerular matrix accumulation results, at least in part, from decreased activity of the PA/plasmin/gelatinase cascade. Specifically we postulate that decreased activity of the cascade results from an imbalance in the relative amounts of tPA and PAI-1 (the major tPA inhibitor) caused by increased production of TGF-beta in response to elevated glucose levels. In addition, we postulate that glycation of the glomerular ECM and serum proteins may play important roles in attenuating ECM degradation.

Our Specific Aims are:

1. To identify the specific function of each component of the PA/plasmin/gelatinase cascade in ECM degradation by cultured mesangial cells. We will examine ECM degradation by cultured mesangial cells which have been: A. obtained from mice with gene deletions (knockouts) for tPA, PAI-1, uPA, and both tPA and uPA; B. stably transfected with expression vectors containing the cDNAs for tPA, uPA, PAI-1, and a PAI-1 resistant tPA.

2. To examine the effects of TGF-beta and elevated glucose levels on ECM degradation and the levels of tPA and PAI-1 in cultured human mesangial cells. Utilizing cultured human and mouse "knockout" mesangial cells we will examine the effects of TGF-beta (0.1-1.0 ng/ml) and elevated glucose (20 and 30 mM) on ECM degradation and the levels (mRNA, protein, activity) of tPA and PAI-1. We will also examine the effects of glycation of the ECM and glycated serum albumin on ECM degradation and the levels of tPA and PAI-1 in cultured mesangial cells.

3. To examine the role of decreased activity of the PA/plasmin/gelatinase cascade in ECM accumulation in diabetic nephropathy. A. We will examine the levels (mRNA, protein, activity) of tPA and PAI-1 in glomeruli isolated from rats with streptozotocin (STZ)-induced diabetes prior to glomerular ECM accumulation. B. We will examine the ability of STZ to induce ECM accumulation in glomeruli obtained from mice with homozygous gene deletions for tPA, PAI-1, and the tPA-uPA double deletion.

These studies will provide new information concerning the mechanisms of mesangial matrix catabolism, its regulation, and the potential role of decreased ECM degradation as a pathogenic mechanism of diabetic nephropathy.

Publications

List of recent publications.

Current Research Grants

NIH - PA/Plasmin/Gelatinase Cascade in Diabetic Nephropathy