Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent years, accumulating evidence indicates a biological function for proinsulin C-peptide. These results challenge the traditional view that C-peptide is essentially inert and only useful as a surrogate marker of insulin release. Accordingly, it is now clear that C-peptide binds with high affinity to cell membranes, probably to a pertussis-toxin-sensitive G-protein-coupled receptor. Subsequently, multiple signalling pathways are potently and dose-dependently activated in multiple cell types by C-peptide with the resulting activation of gene transcription and altered cell phenotype. In diabetic animals and Type 1 diabetic patients, short-term studies indicate that C-peptide also enhances glucose disposal and metabolic control. Furthermore, results derived from animal models and clinical studies in Type 1 diabetic patients suggest a salutary effect of C-peptide in the prevention and amelioration of diabetic nephropathy and neuropathy. Therefore a picture of Type 1 diabetes as a dual-hormone-deficiency disease is developing, suggesting that the replacement of C-peptide alongside insulin should be considered in its management.
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PMID:Cellular and physiological effects of C-peptide. 1924 12

Oxidative stress is thought to be one of the underlying mechanisms of diabetic microvascular complications such as diabetic nephropathy and diabetic retinopathy (DRP). Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthase inhibitor and increased by oxidative stress. Apelin is an endogenous ligand for human orphan G-protein-coupled receptor, APJ and increases NO generation. In this study, our aim was to evaluate ADMA and apelin levels in diabetic patients with or without retinopathy and their relationships between retinopathy stages and metabolic parameters. Seventy-nine diabetic patients were included into the study and classified into three groups. Group 1 consisted of 41 patients with no DRP (NDRP), group 2 consisted of 23 patients with nonproliferative DRP (NPDRP), and group 3 consisted of 15 patients with proliferative DRP (PDRP). Plasma ADMA and apelin levels were found to be similar in all groups. But, there was a positive correlation between apelin levels and urinary albumin/creatinine ratio. Further studies involving larger patients populations and healthy controls should be done to clarify the pathogenetic significance of ADMA and apelin in diabetic microvascular complications.
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PMID:Plasma apelin and asymmetric dimethylarginine levels in type 2 diabetic patients with diabetic retinopathy. 1976 42

Although long believed to be inert, C-peptide has now been shown to have definite biological effects both in vitro and in vivo in diabetic animals and in patients with type 1 diabetes. These effects point to a protective action of C-peptide against the development of diabetic microvascular complications. Underpinning these observations is undisputed evidence of C-peptide binding to a variety of cell types at physiologically relevant concentrations, and the downstream stimulation of multiple cell signaling pathways and gene transcription via the activation of numerous transcription factors. These pathways affect such fundamental cellular processes as re-absorptive and/or secretory phenotype, migration, growth, and survival. Whilst the receptor remains to be identified, experimental data points strongly to the existence of a specific G-protein-coupled receptor for C-peptide. Of the cell types studied so far, kidney tubular cells express the highest number of C-peptide binding sites. Accordingly, C-peptide exerts major effects on the function of these cells, and in the context of diabetic nephropathy appears to antagonise the pathophysiological effects of major disease mediators such as TGFbeta1 and TNFalpha. Therefore, based on its cellular activity profile C-peptide appears well positioned for development as a therapeutic tool to treat microvascular complications in type 1 diabetes.
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PMID:C-Peptide and its intracellular signaling. 2003 3

Insulin and C-peptide are secreted by pancreatic beta cells in equimolar amounts. Although C-peptide has long been believed to have no biological function, in recent years this molecule has been recognized as an independent hormone with a specific G-protein-coupled receptor. Recent evidence suggests that C-peptide may also have a specific nephroprotective effect, particularly in cases of diabetic nephropathy. In animal models of diabetes this beneficial effect has been repeatedly confirmed. Contradictory results have been obtained in humans: on the one hand it was shown that patients with diabetic nephropathy have lower plasma levels of C-peptide than patients with diabetes of similar duration and normal renal function; on the other hand it is also evident that patients affected by type 2 diabetes develop nephropathy even in the presence of high plasma levels of C-peptide, suggesting that in humans C-peptide is likely to have multifaceted activity. This review describes the different arguments supporting or contrasting the notion of C-peptide as a potential new therapy for diabetic nephropathy. It is possible that only a well performed, large-scale clinical study with careful evaluation of the positive and negative effects of C-peptide will finally clarify whether C-peptide reintegration in patients with type 1 diabetes is able to prevent the development and/or control the progression of diabetic nephropathy.
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PMID:[Role of C-peptide in the pathogenesis of diabetic nephropathy]. 2054 17

Ang-(1-7) [angiotensin-(1-7)] is a biologically active heptapeptide component of the RAS (renin-angiotensin system), and is generated in the kidney at relatively high levels, via enzymatic pathways that include ACE2 (angiotensin-converting enzyme 2). The biological effects of Ang-(1-7) in the kidney are primarily mediated by interaction with the G-protein-coupled receptor Mas. However, other complex effects have been described that may involve receptor-receptor interactions with AT(1) (angiotensin II type 1) or AT(2) (angiotensin II type 2) receptors, as well as nuclear receptor binding. In the renal vasculature, Ang-(1-7) has vasodilatory properties and it opposes growth-stimulatory signalling in tubular epithelial cells. In several kidney diseases, including hypertensive and diabetic nephropathy, glomerulonephritis, tubulointerstitial fibrosis, pre-eclampsia and acute kidney injury, a growing body of evidence supports a role for endogenous or exogenous Ang-(1-7) as an antagonist of signalling mediated by AT(1) receptors and thereby as a protector against nephron injury. In certain experimental conditions, Ang-(1-7) appears to paradoxically exacerbate renal injury, suggesting that dose or route of administration, state of activation of the local RAS, cell-specific signalling or non-Mas receptor-mediated pathways may contribute to the deleterious responses. Although Ang-(1-7) has promise as a potential therapeutic agent in humans with kidney disease, further studies are required to delineate its signalling mechanisms in the kidney under physiological and pathophysiological conditions.
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PMID:Angiotensin-(1-7) in kidney disease: a review of the controversies. 2263 21

CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer. These disease associations have motivated numerous preclinical studies and clinical trials (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2-chemokine axis. To aid drug discovery efforts, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein-protein interactions, receptor-chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.
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PMID:Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. 2792 28