Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of the renin-angiotensin-aldosterone system (RAAS) on the development of insulin resistance and type 2 diabetes (T2DM) is an area of growing interest. Most of the deleterious actions of the RAAS on insulin signals appear to be mediated through activation of the serine/threonine kinase, oxidative stress and tissue-inflammation in insulin-sensitive organs. Both experimental and clinical studies demonstrated that angiotensin II (Ang II) and aldosterone could play a role in the development of insulin resistance, diabetes and cardiovascular diseases. Large randomized clinical trials revealed that blockade of the RAAS with either angiotensin I converting enzyme inhibitors or AT1 receptor blockers results in decreased T2DM incidence, with a minor attenuation of markers for insulin resistance. This review focuses on the role of RAAS in the pathogenesis of insulin resistance, as well as on clinical relevance of RAAS blockade in the prevention and treatment of the metabolic syndrome and pre-diabetes.
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PMID:[RAAS and insulin resistance]. 2301 1

Angiotensin (Ang) II, the main effector of the renin-angiotensin system, has been implicated in the pathogenesis of vascular diseases. Ang-(1-7) binds to the G protein-coupled Mas receptor (MasR) and can exert vasoprotective effects. We investigated the effects and underlying mechanisms of Ang-(1-7) on Ang II-induced dysfunction and oxidative stress in human brain microvascular endothelial cells (HbmECs). The pro-apoptotic activity, reactive oxygen species (ROS) and nitric oxide (NO) productions in HbmECs were measured. The protein expressions of nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), serine/threonine kinase (Akt), endothelial nitric oxide synthase (eNOS) and their phosphorylated forms (p-Akt and p-eNOS) were examined by western blot. MasR antagonist and phosphatidylinositol-3-kinase (PI3K) inhibitor were used for receptor/pathway verification. We found that Ang-(1-7) suppressed Ang II-induced pro-apoptotic activity, ROS over-production and NO reduction in HbmECs, which were abolished by MasR antagonist. In addition, Ang-(1-7) down-regulated the expression of Nox2, and up-regulated the ratios of p-Akt/Akt and its downstream p-eNOS/eNOS in HbmECs. Exposure to PI3K inhibitor partially abrogated Ang-(1-7)-mediated protective effects in HbmECs. Our data suggests that Ang-(1-7)/MasR axis protects HbmECs from Ang II-induced dysfunction and oxidative stress via inhibition of Nox2/ROS and activation of PI3K/NO pathways.
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PMID:Angiotensin-(1-7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways. 2610 Nov 59

The mineralocorticoid hormone aldosterone plays a crucial role in the control of Na+ and K+ balance, blood volume, and arterial blood pressure, by acting in the aldosterone-sensitive distal nephron (ASDN) and stimulating a complex transcriptional, translational, and cellular program. Because the complexity of the aldosterone response is still not fully appreciated, we aimed at identifying new elements in this pathway. Here, we demonstrate that the expression of the proto-oncogene PIM3 (Proviral Integration Site of Moloney Murine Leukemia Virus 3), a serine/threonine kinase belonging to the calcium/calmodulin-regulated group of kinases, is stimulated by aldosterone in vitro (mCCDcl1 cells), ex vivo (mouse kidney slices), and in vivo in mice. Characterizing a germline Pim3- / - mouse model, we found that these mice have an upregulated Renin-Angiotensin-Aldosterone System (RAAS), with high circulating aldosterone and plasma renin activity levels on both standard or Na+ -deficient diet. Surprisingly, we did not observe any obvious salt-losing phenotype in Pim3 KO mice as shown by normal blood pressure, plasma and urinary electrolytes, as well as unchanged expression levels of the major Na+ transport proteins. These observations suggest that the potential effects of the loss of the Pim3 gene are physiologically compensated. Indeed, the 2 other family members of the PIM kinase family, PIM1 and PIM2 are upregulated in the kidney of Pim3- / - mice, and may therefore be involved in such compensation. In conclusion, our data demonstrate that the PIM3 kinase is a novel aldosterone-induced protein, but its precise role in aldosterone-dependent renal homeostasis remains to be determined.
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PMID:The serine-threonine kinase PIM3 is an aldosterone-regulated protein in the distal nephron. 3139 90

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and is strongly associated with cardiovascular mortality. Given the pandemic of obesity and diabetes, the elucidation of the molecular underpinnings of DKD and establishment of effective therapy are urgently required. Studies over the past decade have identified the activated renin-angiotensin system (RAS) and hemodynamic changes as important therapeutic targets. However, given the residual risk observed in patients treated with RAS inhibitors and/or sodium glucose co-transporter 2 inhibitors, the involvement of other molecular machinery is likely, and the elucidation of such pathways represents fertile ground for the development of novel strategies. Rho-kinase (ROCK) is a serine/threonine kinase that is under the control of small GTPase protein Rho. Many fundamental cellular processes, including migration, proliferation, and survival are orchestrated by ROCK through a mechanism involving cytoskeletal reorganization. From a pathological standpoint, several analyses provide compelling evidence supporting the hypothesis that ROCK is an important regulator of DKD that is highly pertinent to cardiovascular disease. In cell-based studies, ROCK is activated in response to a diverse array of external stimuli associated with diabetes, and renal ROCK activity is elevated in the context of type 1 and 2 diabetes. Experimental studies have demonstrated the efficacy of pharmacological or genetic inhibition of ROCK in the prevention of diabetes-related histological and functional abnormalities in the kidney. Through a bird's eye view of ROCK in renal biology, the present review provides a conceptual framework that may be widely applicable to the pathological processes of multiple organs and illustrate novel therapeutic promise in diabetology.
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PMID:ROCK Inhibition May Stop Diabetic Kidney Disease. 3315 Feb 49