Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0730345 (microalbuminuria)
 4,018 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-glucose-induced activation of mesangial cell protein kinase C (PKC) contributes significantly to the pathogenesis of diabetic nephropathy. Excess glucose metabolism through the polyol pathway leads to de novo synthesis of both diacylglyerol (DAG) and phosphatidic acid, which may account for increased mesangial cell PKC-alpha, -beta, -delta, -epsilon, and -zeta activation/translocation observed within 48-h exposure to high glucose. Raised intracellular glucose causes generation of reactive oxygen species that may directly activate PKC isozymes and enhance their reactivity to vasoactive peptide signaling. In both diabetic rodent models of diabetes and cultured mesangial cells, PKC-beta appears to be the key isozyme required for the enhanced expression of transforming growth factor-beta(1), initiation of early accumulation of mesangial matrix protein, and increased microalbuminuria. Enhanced collagen IV expression by mesangial cells in response to vasoactive peptide hormone stimulation, e.g., endothelin-1, requires PKC-beta, -delta, -epsilon and -zeta. Loss of mesangial cell contractility to potent vasoactive peptides and coincident F-actin disassembly are due to high-glucose-activation of PKC-zeta. Inhibition of mesangial cell PKC isozyme activation in high glucose may prove to be the next important treatment for diabetic nephropathy.
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PMID:Mesangial cell protein kinase C isozyme activation in the diabetic milieu. 1199 13

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor that comprises the primary molecular target for thiazolidinedione (TZD) insulin-sensitizing drugs. Whilst expressed in many tissues in humans, its abundant expression in adipose tissue is believed to be the focal point through which TZDs regulate genes involved in glucose and lipid metabolism and via which these agents ultimately improve the hyperglycemia of type 2 diabetes. However, TZDs exhibit many additional properties, not least an array of effects which suggest a broad attack on the inflammatory process. Thus, TZDs have been shown to reduce plasma levels of the chemokine, monocyte chemotactic protein-1 (MCP-1), the anti-fibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1), the endothelial cell adhesion molecules, e-selectin and inter-cellular adhesion molecule-1 (ICAM-1), the leucocyte-activating molecule, CD40L, and the tissue-remodeling enzyme, matrix metalloproteinase-9 (MMP-9). Further tangible evidence of a reduction by TZDs of systemic inflammation in patients with the classical metabolic syndrome stems from falls in the white blood cell count, P-selectin-positive platelets and in the acute-phase inflammatory proteins, C-reactive protein, serum amyloid A and fibrinogen. At the tissue level, TZDs improve vascular endothelial function, and reduce the rate of progression of intimal-medial thickening of the carotid artery and the microalbuminuria of type 2 diabetes. Further, TZDs have been shown to be efficacious in inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic steatohepatitis (NASH). In the case of the latter, a broad spectrum of TZD-related properties is visible. Here, these drugs improve insulin sensitivity for glucose metabolism, reduce hyperinsulinemia, hepatic steatosis, inflammation and fibrosis, and lower the circulating levels of liver transaminases (ALT, AST), alkaline phosphatase and gamma glutamyl transferase. These effects in humans are also well-supported by investigative animal and in vitro studies. The ameliorative effects on liver fibrosis are of particular interest since they suggest that TZDs are able to activate a program of corrective tissue-remodeling. The basis for this action may be partly an ability to inhibit matrix protein secretion by hepatic stellate cells. An analogous action has also been seen in kidney mesangial cells. In conclusion, TZDs are important new drugs, presently indicated for the treatment of type 2 diabetes but with a spectrum of properties which suggests their potential for treating a number of degenerative inflammatory diseases, including NASH. However, full-scale, long-term clinical trials are needed with TZDs to test their potential to treat NASH, not least because of the (hepatotoxic) legacy of the prototype TZD, troglitazone, but also in view of the escalating burden of liver disease which is accompanying the increasing global prevalence of clinical obesity and type 2 diabetes.
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PMID:Thiazolidinediones: Pleiotropic drugs with potent anti-inflammatory properties for tissue protection. 1619 19