Metabolic Disease and Receptor Cleavage

Unchecked Proteolytic Receptor Cleavage - An Early Form of Autodigestion

A Mechanism for Type II Diabetes in Hypertension and their (numerous) Co-Morbidities

Diabetes and hypertension often occur in the same individual, often together with other complications.

We discovered and investigate a mechanism for cell and organ dysfunction in hypertension and diabetes due to the presence of unchecked proteolytic activity, e.g. serine proteases and matrix-degrading metalloproteinases (MMPs). Cleavage of a membrane receptor by extracellular proteases leads to loss of receptor signaling and its associated cell function. Here are some examples.

Adrenergic Receptor Cleavage and Elevated Blood Pressure

An unchecked proteolytic activity cleaves the extracellular domain of the beta-2 adrenergic receptor in arterioles, causing arterioles to contract and thereby raising the central blood pressure (Rodriguez et al.).

Insulin Receptor Cleavage, Insulin Resistance and Type II Diabetes

Proteolytic cleavage of the extracellular domain of the insulin receptor leads to loss of insulin signaling and glucose transport into the cell, i.e. insulin-resistance (Type II Diabetes) (DeLano et al.).

Endothelial Growth Factor Cleavage, Apoptosis and Capillary Rarefaction

Extracellular domain cleavage of the vascular endothelial growth factor receptor 2 (VEGFR-2) leads to endothelial apoptosis and loss of capillaries (capillary network rarefaction) (a. Tran et al. ; b. Tran et al.).

Leukocyte -Endothelium Adhesion Defect and Immune Suppression

Proteolytic cleavage of the extracellular domain of leukocyte adhesion receptors CD18, P-selectin, PSGL-1, ICAM-1 reduces the interaction with the endothelium (DeLano et al., Chen AY et al. ) and a defect in leukocyte migration into the tissue (Fukuda).

Glycocalyx Cleavage

Cleavage of the glycocalyx leads to lack of macrophage attachment to older erythrocytes (Pot et al. ).

Defective Fluid Shear Stress Response in Leukocytes

Proteolytic cleavage of the f-MLP receptor, a mechanosensor on neutrophils (Makino et al., 2006), leads to loss of the ability of neutrophils to retract pseudopods on activated neutrophils (Chen, A.Y. et al.) and contributes to elevated capillary hemodynamic resistance (Fukuda et al.).

Leptin Receptor Cleavage, Leptin Resistance with Loss of Satiety

During a high fat diet proteolytic cleavage of the extracellular domain of the leptin receptor in the brain leads to loss of leptin signaling and satiety, i.e. weight gain. (Mazor et al.).

Blockade of Receptor Cleavage

Reduction of MMP activity (e.g. by chronic pharmacological treatment) serves to restore receptor densities and consequently attenuates the diverse cellular and cardiovascular defects.

The Essence

These results support the hypothesis that the numerous co-morbidities in Hypertension, Type II Diabetes or metabolic disease are triggered by proteolytic cleavage of receptors. The metabolic disease may be an early form of Autodigestion (Mazur et al.).

Future Opportunities:

  • To develop in patients a proteomic-wide analysis of degrading enzymes, their activities, and peptides they generate.
  • To determine gene expression and epigenetic control of receptors in the presence of receptor cleavage and autodigestion.

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Extracellular Domain Density of the Insulin Receptor on Control Human Leukocytes after Exposure to Plasma after Normal Diet (top row) and a High Fat Diet (bottom row).