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Renalase: its role as a cytokine, and an update on its association with type 1 diabetes and ischemic stroke.

ABSTRACT: Remarkable progress has been achieved over the past 2 years in understanding the cellular actions of renalase, its pathophysiology and potential therapeutic utility.There has been a paradigm shift in our thinking about the mechanisms underlying the cellular actions of renalase. We now understand that, independent of its enzymatic properties, renalase functions as a signaling molecule, a cytokine that interacts with a yet-to-be identified plasma membrane receptor(s) to activate protein kinase B and the mitogen-activated protein kinase pathway. These signaling properties are critical to its cytoprotective effects. New information regarding renalase's enzymatic function as an ?-nicotinamide adenine dinucleotide oxidase/anomerase will be reviewed. Lastly, we will discuss the association of certain single nucleotide polymorphisms in the renalase gene with type 1 diabetes and with ischemic stroke, and the clinical implications of these findings.The consistent association of renalase single nucleotide polymorphisms and the development of type 1 diabetes is a great interest particularly because we now understand that renalase functions as a cytokine. Future work on renalase should focus on exploring the identity of its receptor(s), and its potential role as an immune modulator.

SUBMITTER: Guo X

PROVIDER: S-EPMC4383282 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Renalase: its role as a cytokine, and an update on its association with type 1 diabetes and ischemic stroke.

Guo Xiaojia X Wang Ling L Velazquez Heino H Safirstein Robert R Desir Gary V GV

Current opinion in nephrology and hypertension 20140901 5

<h4>Purpose of review</h4>Remarkable progress has been achieved over the past 2 years in understanding the cellular actions of renalase, its pathophysiology and potential therapeutic utility.<h4>Recent findings</h4>There has been a paradigm shift in our thinking about the mechanisms underlying the cellular actions of renalase. We now understand that, independent of its enzymatic properties, renalase functions as a signaling molecule, a cytokine that interacts with a yet-to-be identified plasma m ...[more]

PMID: 24992568

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Project description:BackgroundHypertension is one of the strongest risk factors for stroke in the general population, while systolic blood pressure has been shown to independently increase the risk of stroke in type 1 diabetes. The aim of this study was to elucidate the association between different blood pressure variables and risk of stroke in type 1 diabetes, and to explore potential nonlinearity of this relationship.MethodsWe included 4105 individuals with type 1 diabetes without stroke at baseline, participating in the nationwide Finnish Diabetic Nephropathy Study. Mean age at baseline was 37.4 ± 11.9 years, median duration of diabetes 20.9 (interquartile range 11.5-30.4) years, and 52% were men. Office systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Based on these pulse pressure (PP) and mean arterial pressure (MAP) were calculated. Strokes were classified based on medical and autopsy records, as well as neuroimaging. Cox proportional hazard models were performed to study how the different blood pressure variables affected the risk of stroke and its subtypes.ResultsDuring median follow-up time of 11.9 (9.21-13.9) years, 202 (5%) individuals suffered an incident stroke; 145 (72%) were ischemic and 57 (28%) hemorrhagic. SBP, DBP, PP, and MAP all independently increased the risk of any stroke. SBP, PP, and MAP increased the risk of ischemic stroke, while SBP, DBP, and MAP increased the risk of hemorrhagic stroke. SBP was strongly associated with stroke with a hazard ratio of 1.20 (1.11-1.29)/10 mmHg. When variables were modeled using restricted cubic splines, the risk of stroke increased linearly for SBP, MAP, and PP, and non-linearly for DBP.ConclusionsThe different blood pressure variables are all independently associated with increased risk of stroke in individuals with type 1 diabetes. The risk of stroke, ischemic stroke, and hemorrhagic stroke increases linearly at blood pressure levels less than the current recommended treatment guidelines.

Project description:Type 2 diabetes (T2D) is an independent risk factor for acute ischemic stroke (AIS), but the underlying mechanisms remain elusive. Because the gut microbiota plays a causal role in both T2D and AIS, we wondered whether gut dysbiosis in T2D aggravates stroke progression. We recruited 35 T2D, 90 AIS, 60 AIS with T2D (AIS_T2D) patients, and 55 healthy controls and found that AIS and T2D had an additive effect on AIS_T2D patient gut dysbiosis by exhibiting the largest difference from the heathy controls. In addition, we found that the degree of gut dysbiosis associated with T2D was positively correlated with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin score (mRS), and Essen stroke risk score in patients with AIS, including AIS and AIS_T2D patients. Compared with mice colonized with gut microbiota from healthy controls poststroke modeling, germfree (GF) mice colonized with gut microbiota from T2D patients showed exacerbated cerebral injury and impaired gut barrier function. Specifically, exacerbated brain injury and gut barrier dysfunction in T2D-treated GF mice were significantly associated with a reduction in short-chain fatty acid (SCFA)-producing bacteria. Our study showed that T2D and AIS have an additive effect on AIS_T2D patient gut microbiota dysbiosis. T2D-associated gut microbiota dysbiosis is associated with stroke severity in AIS patients and aggravates stroke progression in mice. IMPORTANCE We demonstrated an additive effect of type 2 diabetes (T2D) and acute ischemic stroke (AIS) on AIS with T2D (AIS_T2D) patient gut microbiota dysbiosis, and gut dysbiosis associated with T2D was positively correlated with stroke severity in AIS patients. Through animal experiments, we found that cerebral injury was exacerbated by fecal microbiota transplantation from T2D patients compared with that from healthy controls, which was associated with a reduction in short-chain fatty acid (SCFA)-producing bacteria. This study provided a novel view that links T2D and AIS through gut microbial dysbiosis.

Dataset Information

Renalase: its role as a cytokine, and an update on its association with type 1 diabetes and ischemic stroke.

Publications

Renalase: its role as a cytokine, and an update on its association with type 1 diabetes and ischemic stroke.

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