- Vascular endothelium dysfunction: a conservative target in metabolic disorders. [Review]
- IRInflamm Res 2018 Jan 25
- CONCLUSIONS: Thus, the cellular and molecular mechanisms underlying diabetes mellitus, hyperhomocysteinemia, hypercholesterolemia hypertension and hyperuricemia leads to an imbalance of phosphorylation and dephosphorylation status of lipid and protein kinase that cause modulation of vascular endothelial L-arginine/nitric oxide synthetase (eNOS), to produce vascular endothelium dysfunction.
- Insulin stimulates uric acid reabsorption via regulating urate transporter 1 and ATP-binding cassette subfamily G member 2. [Journal Article]
- AJAm J Physiol Renal Physiol 2017 Sep 01; 313(3):F826-F834
- Accumulating data indicate that renal uric acid (UA) handling is altered in diabetes and by hypoglycemic agents. In addition, hyperinsulinemia is associated with hyperuricemia and hypouricosuria. How...
Accumulating data indicate that renal uric acid (UA) handling is altered in diabetes and by hypoglycemic agents. In addition, hyperinsulinemia is associated with hyperuricemia and hypouricosuria. However, the underlying mechanisms remain unclear. In this study, we aimed to investigate how diabetes and hypoglycemic agents alter the levels of renal urate transporters. In insulin-depleted diabetic rats with streptozotocin treatment, both UA excretion and fractional excretion of UA were increased, suggesting that tubular handling of UA is altered in this model. In the membrane fraction of the kidney, the expression of urate transporter 1 (URAT1) was significantly decreased, whereas that of ATP-binding cassette subfamily G member 2 (ABCG2) was increased, consistent with the increased renal UA clearance. Administration of insulin to the diabetic rats decreased UA excretion and alleviated UA transporter-level changes, while sodium glucose cotransporter 2 inhibitor (SGLT2i) ipragliflozin did not change renal UA handling in this model. To confirm the contribution of insulin in the regulation of urate transporters, normal rats received insulin and separately, ipragliflozin. Insulin significantly increased URAT1 and decreased ABCG2 levels, resulting in increased UA reabsorption. In contrast, the SGLT2i did not alter URAT1 or ABCG2 levels, although blood glucose levels were similarly reduced. Furthermore, we found that insulin significantly increased endogenous URAT1 levels in the membrane fraction of NRK-52E cells, the kidney epithelial cell line, demonstrating the direct effects of insulin on renal UA transport mechanisms. These results suggest a previously unrecognized mechanism for the anti-uricosuric effects of insulin and provide novel insights into the renal UA handling in the diabetic state.
- URAT1 inhibition by ALPK1 is associated with uric acid homeostasis. [Journal Article]
- RRheumatology (Oxford) 2017 Apr 01; 56(4):654-659
- CONCLUSIONS: Elevated ALPK1 expression decreased URAT1 expression. ALPK1 might prevent the impact of urate reuptake via SLC22A12 and appeared to be negatively associated with gout. ALPK1 is a potential repressor of URAT1 protein expression.
- Melatonin protects against uric acid-induced mitochondrial dysfunction, oxidative stress, and triglyceride accumulation in C2C12 myotubes. [Journal Article]
- JAJ Appl Physiol (1985) 2017 Apr 01; 122(4):1003-1010
- Excess uric acid has been shown to induce oxidative stress, triglyceride accumulation, and mitochondrial dysfunction in the liver and is an independent predictor of type-2 diabetes. Skeletal muscle p...
Excess uric acid has been shown to induce oxidative stress, triglyceride accumulation, and mitochondrial dysfunction in the liver and is an independent predictor of type-2 diabetes. Skeletal muscle plays a dominant role in type 2 diabetes and presents a large surface area to plasma uric acid. However, the effects of uric acid on skeletal muscle are underinvestigated. Our aim was therefore to characterize the effects of excessive uric acid on oxidative stress, triglyceride content, and mitochondrial function in skeletal muscle C2C12 myotubes and assess how these are modulated by the antioxidant molecule melatonin. Differentiated C2C12 myotubes were exposed to 750 µM uric acid or uric acid + 10 nM melatonin for 72 h. Compared with control, uric acid increased triglyceride content by ~237%, oxidative stress by 32%, and antioxidant capacity by 135%. Uric acid also reduced endogenous ROUTINE respiration, complex II-linked oxidative phosphorylation, and electron transfer system capacities. Melatonin counteracted the effects of uric acid without further altering antioxidant capacity. Our data demonstrate that excess uric acid has adverse effects on skeletal muscle similar to those previously reported in hepatocytes and suggest that melatonin at a low physiological concentration of 10 nM may be a possible therapy against some adverse effects of excess uric acid.NEW & NOTEWORTHY Few studies have investigated the effects of uric acid on skeletal muscle. This study shows that hyperuricemia induces mitochondrial dysfunction and triglyceride accumulation in skeletal muscle. The findings may explain why hyperuricemia is an independent predictor of diabetes.
- Elevated circulatingadenosine deaminase activity in women with preeclampsia: association with pro-inflammatory cytokine production and uric acid levels. [Journal Article]
- PHPregnancy Hypertens 2016; 6(4):400-405
- CONCLUSIONS: An elevation in ADA activity in women with PE may contribute to their increased levels of uric acid and pro-inflammatory immune activity.
- Roles of the NLRP3 inflammasome in the pathogenesis of diabetic nephropathy. [Review]
- PRPharmacol Res 2016; 114:251-264
- Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and persistent inflammation in circulatory and renal tissues is an important pathophysiological basis for DN. The essence of ...
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and persistent inflammation in circulatory and renal tissues is an important pathophysiological basis for DN. The essence of the microinflammatory state is the innate immune response, which is central to the occurrence and development of DN. Members of the inflammasome family, including both "receptors" and "regulators", are key to the inflammatory immune response. Nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) and other inflammasome components are able to detect endogenous danger signals, resulting in activation of caspase-1 as well as interleukin (IL)-1β, IL-18 and other cytokines; these events stimulate the inflammatory cascade reaction, which is crucial for DN. Hyperglycaemia, hyperlipidaemia and hyperuricaemia can activate the NLRP3 inflammasome, which then mediates the occurrence and development of DN through the K+ channel model, the lysosomal damage model and the active oxygen cluster model. In this review, we survey the involvement of the NLRP3 inflammasome in various signalling pathways and highlight different aspects of their influence on DN. We also explore the important effects of the NLRP3 inflammasome on kidney function and structural changes that occur during DN development and progression. It is becoming more evident that NLRP3 inflammasome targeting has therapeutic potential for the treatment of DN.
- Genetic background of uric acid metabolism in a patient with severe chronic tophaceous gout. [Case Reports]
- CCClin Chim Acta 2016 Sep 01; 460:46-9
- Hyperuricemia depends on the balance of endogenous production and renal excretion of uric acid. Transporters for urate are located in the proximal tubule where uric acid is secreted and extensively r...
Hyperuricemia depends on the balance of endogenous production and renal excretion of uric acid. Transporters for urate are located in the proximal tubule where uric acid is secreted and extensively reabsorbed: secretion is principally ensured by the highly variable ABCG2 gene. Enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) plays a central role in purine metabolism and its deficiency is an X-linked inherited metabolic disorder associated with clinical manifestations of purine overproduction. Here we report the case of a middle-aged man with severe chronic tophaceous gout with a poor response to allopurinol and requiring repeated surgical intervention. We identified the causal mutations in the HPRT1 gene, variant c.481G>T (p.A161S), and in the crucial urate transporter ABCG2, a heterozygous variant c.421C>A (p.Q141K). This case shows the value of an analysis of the genetic background of serum uric acid.
- [Nutritional therapy of gout]. [Review]
- TUTher Umsch 2016; 73(3):153-8
- Nutrition and nutritional behaviours have been found to play a major role in the development of gout. Studies show that body mass index (BMI), as well as excessive intake of alcoholic beverages, meat...
Nutrition and nutritional behaviours have been found to play a major role in the development of gout. Studies show that body mass index (BMI), as well as excessive intake of alcoholic beverages, meat, soft drinks and fruit juices increase the risk of developing gout. Similarly, dairy products and coffee have been seen to decrease the risk of hyperuricemia and gout, as they increase the excretion of uric acid. Flares of gout are often caused by large meals and high alcohol consumption. Each additional intake of meat portion per day increases the risk of gout by 21 %. Taking total alcohol consumption into account, the risk of gout increases after one to two standard drinks. In contrast to previous assumptions purine-rich plant foods like legumes and vegetables do not increase the risk of gout. The current dietary guidelines take into account nutritional factors, which not only consider purine intake, but also their endogenous production and their influence on renal excretion. A balanced diet based on the Swiss healthy eating guideline pyramid as well as the Mediterranean diet is appropriate for this patient population. The treatment of gout is multi-faceted, since this patient population presents other comorbidities such as obesity, diabetes mellitus, dyslipidemia and hypertension. Collectively, these risk factors are diet dependent and require a treatment strategy that is centered on modifying one's nutrition and nutritional behaviours. The aim of such therapy is to educate the patient as well as treat the accompanying comorbidities with the goal of decreasing serum uric acid values. Motivated patients require consultation and follow-up care in order to be able to actively decrease the serum uric acid.
- Uric Acid for Cardiovascular Risk: Dr. Jekyll or Mr. Hide? [Review]
- DDiseases 2016 Feb 26; 4(1)
- Uric acid (UA) is a potent endogenous antioxidant. However, high concentrations of this molecule have been associated with cardiovascular disease (CVD) and renal dysfunction, involving mechanisms tha...
Uric acid (UA) is a potent endogenous antioxidant. However, high concentrations of this molecule have been associated with cardiovascular disease (CVD) and renal dysfunction, involving mechanisms that include oxidative stress, inflammatory processes, and endothelial injury. Experimental and in vitro results suggest that this biomarker behaves like other antioxidants, which can shift from the physiological antioxidant action to a pro-oxidizing effect according to their level and to microenvironment conditions. However, data on patients (general population or CAD cohorts) are controversial, so the debate on the role of hyperuricemia as a causative factor for CVD is still ongoing. Increasing evidence indicates UA as more meaningful to assess CVD in women, even though this aspect needs deeper investigation. It will be important to identify thresholds responsible for UA "biological shift" from protective to harmful effects in different pathological conditions, and according to possible gender-related differences. In any case, UA is a low-tech and inexpensive biomarker, generally performed at patient's hospitalization and, therefore, easily accessible information for clinicians. For these reasons, UA might represent a useful additive tool as much as a CV risk marker. Thus, in view of available evidence, progressive UA elevation with levels higher than 6 mg/dL could be considered an "alarm" for increased CV risk.
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- Hyperuricemia and nonalcoholic fatty liver disease: from bedside to bench and back. [Review]
- HIHepatol Int 2016; 10(2):286-93
- Uric acid is the end product of dietary or endogenous purines degradation, and hyperuricemia is one of the most common metabolic disorders. It has been widely accepted that hyperuricemia increases ri...
Uric acid is the end product of dietary or endogenous purines degradation, and hyperuricemia is one of the most common metabolic disorders. It has been widely accepted that hyperuricemia increases risks of gout, cardiovascular diseases, and type 2 diabetes. A growing body of evidence, comprising a great deal of cross-sectional studies and several prospective ones, also indicates that hyperuricemia is associated with increased prevalence, incidence and disease severity of non-alcoholic fatty liver disease (NAFLD). On the contrary, NAFLD can predict hyperuricemia as well. However, no causal relationship can be drawn from this point. With a well-established relationship between uric acid and NAFLD prevalence as well as disease severity in addition to the role of potential therapeutic target, the prognostic role of uric acid is also worth investigating. Further studies should focus on the prospective role of uric acid on NAFLD progression and its underlying mechanisms, as well as its clinical implications.