Grant: Project Grant - PA: Nutrition, Metabolism and Diabetes

Because it has been associated with many diseases, chronic inflammation and fibrosis are major cause of tissue dysfunction causing global morbidity and mortality. Patients with longstanding diabetes often exhibit extensive fibrotic lesions in the heart, kidney and liver. We have uncovered a potential new mechanism of diabetes-induced chronic inflammation of infiltrated immune cells by reducing a protein called MKP-2. MKP-2 is a member of the protein phosphatase family that downregulates the activity of important signaling protein involved in cell survival, proliferation and function. Previous observation using genetically modified mice that do not express MKP-2 gene revealed that diabetic animals developed advanced inflammatory cell infiltration in the kidney. Interestingly, rodents that abundantly produce MKP-2 in immune cells were protected from development of tissue inflammation and fibrosis. Thus, a better understanding of the role of MKP-2 in immune cells and how this protein can regulate cellular infiltration, chronic inflammation and development of fibrosis will provide a potential new target to treat diabetic kidney disease. The aim of the present proposal will investigate the role of MKP-2 causing kidney inflammation and fibrosis. To accomplish this aim, we will use mice that MKP-2 has been genetically modified to evaluate its cellular mechanisms implicated in diabetic models of kidney fibrosis. Furthermore, we will use several methods to specifically manipulate the protein expression level of MKP-2 in immune/inflammatory and vascular cells present in the kidney to investigate its role on tissue infiltration, cellular repair function, chronic inflammation vascular dysfunction and fibrosis. This proposal will provide a better understanding of the mechanisms underlying infiltration of immune cells and vascular dysfunction related to diabetes, offering additional tools to develop new strategies to prevent and reverse diabetic kidney diseases.