scholarly journals Research Advances in the Mechanisms of Hyperuricemia-Induced Renal Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Hong-yong Su ◽  
Chen Yang ◽  
Dong Liang ◽  
Hua-feng Liu
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Independent Risk Factor ◽  
Molecular Mechanisms ◽  
Renal Diseases ◽  
Crystal Deposition ◽  
Urate Crystal ◽  
Excessive Accumulation

Uric acid is the end product of purine metabolism in humans, and its excessive accumulation leads to hyperuricemia and urate crystal deposition in tissues including joints and kidneys. Hyperuricemia is considered an independent risk factor for cardiovascular and renal diseases. Although the symptoms of hyperuricemia-induced renal injury have long been known, the pathophysiological molecular mechanisms are not completely understood. In this review, we focus on the research advances in the mechanisms of hyperuricemia-caused renal injury, primarily on oxidative stress, endothelial dysfunction, renal fibrosis, and inflammation. Furthermore, we discuss the progress in hyperuricemia management.

Abstract 371: DPPIV Inhibitor MK0626 Prevents Western Diet Induced Renal Injury via Suppression of Kidney Tissue Ras

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Ravi Nistala ◽  
Javad Habibi ◽  
Annayya Aroor ◽  
Melvin R Hayden ◽  
Mona Garro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Renal Injury ◽  
Sodium Excretion ◽  
The United States ◽  
Western Diet ◽  
Ang Ii ◽  
High Fructose ◽  
Dppiv Inhibitor ◽  
And Oxidative Stress

Objectives: Obesity is an independent risk factor for development and progression of renal injury. High fructose corn syrup consumption has coincided with the obesity epidemic in the United States. High fructose (60%) diets have been demonstrated to be associated with elevation in BP and worsening insulin resistance along with renal injury via increased hepatic production of uric acid. Recently, DPPIV inhibitors have been shown to improve diabetic changes and sodium excretion, effects that are beyond glycemic control. Therefore, the renal protective benefits of DPPIV inhibition in a clinically relevant Western diet fed mouse model were examined. Methods: Mice fed a high fat/high fructose (WD) diet for 16 weeks and given a DPPIV inhibitor MK0626 in their diet were examined for metabolic parameters, inflammation, kidney renin-angiotensin system (RAS) and oxidative stress. Renal injury was assessed by biochemical, immunohistological and electron microscopy techniques. In vitro , angiotensin II (Ang II) effects on OKP-PTCs were assessed for mechanism. Results: MK0626 ameliorated WD-induced increases in serum uric acid, oxidative stress and RAS. WD induced suppression of IL-10 was reversed by MK0626. There was a tendency to improve HOMA-IR by MK0626 but no effect on BP and body weights. Diet induced DPPIV activation in the plasma and kidney of WD mice was abrogated by MK0626 (~80%). WD mice were characterized by increased proteinuria (~3-fold), mesangial expansion and podocyte effacement and these changes were prevented by MK0626. In addition, the PTC endocytosis protein megalin and basilar canalicular network and mitochondrial ultrastructure abnormalities were reversed by MK0626. WD mice had decreased sodium excretion which was improved by MK0626. Ang II directly increased DPPIV activity and sodium hydrogen exchanger activity in PTCs and decreased megalin protein, which was effectively prevented by MK0626. Conclusion: Thus, WD induced increases in DPPIV activity is associated with elevations in uric acid, renal RAS, inflammation and oxidative stress which may result in renal injury. These results suggest that DPPIV inhibitors prevent WD induced renal injury and offer a novel therapy for diabetic and obesity associated renal disease.

scholarly journals Multiple-Purpose Connectivity Map Analysis Reveals the Benefits of Esculetin to Hyperuricemia and Renal Fibrosis

2020 ◽  
Vol 21 (20) ◽  
pp. 7695
Author(s):  
Yiming Wang ◽  
Weikaixin Kong ◽  
Liang Wang ◽  
Tianyu Zhang ◽  
Boyue Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Serum Uric Acid ◽  
Renal Fibrosis ◽  
Nuclear Translocation ◽  
Connectivity Map ◽  
Stress Injury ◽  
Ckd Stage ◽  
Lowering Drug

Hyperuricemia (HUA) is a risk factor for chronic kidney disease (CKD). Serum uric acid (SUA) levels in CKD stage 3–4 patients closely correlate with hyperuricemic nephropathy (HN) morbidity. New uric acid (UA)-lowering strategies are required to prevent CKD. The multiple-purpose connectivity map (CMAP) was used to discover potential molecules against HUA and renal fibrosis. We used HUA and unilateral ureteral occlusion (UUO) model mice to verify renoprotective effects of molecules and explore related mechanisms. In vitro experiments were performed in HepG2 and NRK-52E cells induced by UA. Esculetin was the top scoring compound and lowered serum uric acid (SUA) levels with dual functions on UA excretion. Esculetin exerted these effects by inhibiting expression and activity of xanthine oxidase (XO) in liver, and modulating UA transporters in kidney. The mechanism by which esculetin suppressed XO was related to inhibiting the nuclear translocation of hexokinase 2 (HK2). Esculetin was anti-fibrotic in HUA and UUO mice through inhibiting TGF-β1-activated profibrotic signals. The renoprotection effects of esculetin in HUA mice were associated with lower SUA, alleviation of oxidative stress, and inhibition of fibrosis. Esculetin is a candidate urate-lowering drug with renoprotective activity and the ability to inhibit XO, promote excretion of UA, protect oxidative stress injury, and reduce renal fibrosis.

Urate nephropathy

2015 ◽  
Author(s):  
Duk-Hee Kang ◽  
Mehmet Kanbay
Keyword(s):  
Uric Acid ◽  
Serum Uric Acid ◽  
Crystal Deposition ◽  
Asymptomatic Patients ◽  
Xanthine Oxidase Inhibitors ◽  
Comorbidity Burden ◽  
Urate Nephropathy ◽  
Systemic Disorder ◽  
Urate Crystal ◽  
Uric Acid Nephropathy

Gout is a disorder of purine metabolism, characterized by hyperuricaemia and urate crystal deposition within and around the joints. The recognition of increased comorbidity burden in patients with gout rendered it as a systemic disorder rather than simply a musculoskeletal condition. Gout nephropathy (also known as chronic uric acid nephropathy or urate nephropathy) is a form of chronic tubulointerstitial nephritis, induced by deposition of monosodium urate crystals in the distal collecting ducts and the medullary interstitium, associated with a secondary inflammatory reaction. Other renal histologic changes include arteriolosclerosis, glomerulosclerosis, and tubulointerstitial fibrosis. In patients with urate nephropathy, hypertension is common, but usually there is only mild proteinuria and a slight increase in serum creatinine. The reduction of serum uric acid, using xanthine oxidase inhibitors and perhaps low-purine diet, is the mainstay of therapy. There is current research around the question of whether it is beneficial to lower serum uric acid in asymptomatic patients with renal disease or with cardiovascular risk factors.

Mechanistic Insights of Soluble Uric Acid-related Kidney Disease

2020 ◽  
Vol 27 (30) ◽  
pp. 5056-5066 ◽  
Author(s):  
Pan Jing ◽  
Min Shi ◽  
Liang Ma ◽  
Ping Fu
Keyword(s):  
Uric Acid ◽  
Risk Factor ◽  
Kidney Disease ◽  
Serum Uric Acid ◽  
Independent Risk Factor ◽  
Elevated Serum ◽  
Tubulointerstitial Fibrosis ◽  
Renal Diseases ◽  
Glomerular Hypertrophy ◽  
Progression Of Kidney Disease

Hyperuricemia, defined as the presence of elevated serum uric acid (sUA), could lead to urate deposit in joints, tendons, kidney and other tissues. Hyperuricemia as an independent risk factor was common in patients during the causation and progression of kidney disease. Uric acid is a soluble final product of endogenous and dietary purine metabolism, which is freely filtered in kidney glomeruli where approximately 90% of filtered uric acid is reabsorbed. Considerable studies have demonstrated that soluble uric acid was involved in the pathophysiology of renal arteriolopathy, tubule injury, tubulointerstitial fibrosis, as well as glomerular hypertrophy and glomerulosclerosis. In the review, we summarized the mechanistic insights of soluble uric acid related renal diseases.

Role of the TGF-β/BMP-7/Smad pathways in renal diseases

2012 ◽  
Vol 124 (4) ◽  
pp. 243-254 ◽  
Author(s):  
Xiao-Ming Meng ◽  
Arthur C. K. Chung ◽  
Hui Y. Lan
Keyword(s):  
Renal Injury ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Biological Activities ◽  
Transforming Growth Factor Β ◽  
Renal Diseases ◽  
Ubiquitin E3 Ligase ◽  
Tgf Β1

TGF-β (transforming growth factor-β) and BMP-7 (bone morphogenetic protein-7), two key members in the TGF-β superfamily, play important but diverse roles in CKDs (chronic kidney diseases). Both TGF-β and BMP-7 share similar downstream Smad signalling pathways, but counter-regulate each other to maintain the balance of their biological activities. During renal injury in CKDs, this balance is significantly altered because TGF-β signalling is up-regulated by inducing TGF-β1 and activating Smad3, whereas BMP-7 and its downstream Smad1/5/8 are down-regulated. In the context of renal fibrosis, Smad3 is pathogenic, whereas Smad2 and Smad7 are renoprotective. However, this counter-balancing mechanism is also altered because TGF-β1 induces Smurf2, a ubiquitin E3-ligase, to target Smad7 as well as Smad2 for degradation. Thus overexpression of renal Smad7 restores the balance of TGF-β/Smad signalling and has therapeutic effect on CKDs. Recent studies also found that Smad3 mediated renal fibrosis by up-regulating miR-21 (where miR represents microRNA) and miR-192, but down-regulating miR-29 and miR-200 families. Therefore restoring miR-29/miR-200 or suppressing miR-21/miR-192 is able to treat progressive renal fibrosis. Furthermore, activation of TGF-β/Smad signalling inhibits renal BMP-7 expression and BMP/Smad signalling. On the other hand, overexpression of renal BMP-7 is capable of inhibiting TGF-β/Smad3 signalling and protects the kidney from TGF-β-mediated renal injury. This counter-regulation not only expands our understanding of the causes of renal injury, but also suggests the therapeutic potential by targeting TGF-β/Smad signalling or restoring BMP-7 in CKDs. Taken together, the current understanding of the distinct roles and mechanisms of TGF-β and BMP-7 in CKDs implies that targeting the TGF-β/Smad pathway or restoring BMP-7 signalling may represent novel and effective therapies for CKDs.

Effect of elevated serum uric acid on cisplatin-induced acute renal failure

2007 ◽  
Vol 292 (1) ◽  
pp. F116-F122 ◽  
Author(s):  
Carlos A. Roncal ◽  
Wei Mu ◽  
Byron Croker ◽  
Sirirat Reungjui ◽  
Xiaosen Ouyang ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Acute Renal Failure ◽  
Uric Acid ◽  
Renal Injury ◽  
Elevated Serum ◽  
Urate Oxidase ◽  
Crystal Formation ◽  
Tubular Injury ◽  
Crystal Deposition

Marked hyperuricemia is known to cause acute renal failure via intrarenal crystal deposition. However, recent studies suggest mild hyperuricemia may have vasoactive and proinflammatory effects independent of crystal formation. We therefore tested the hypothesis that mild hyperuricemia might exacerbate renal injury and dysfunction in a model of cisplatin-induced acute renal failure in the rat. Cisplatin was administered to normouricemic and hyperuricemic rats (the latter generated by administering the urate oxidase inhibitor, oxonic acid). Recombinant urate oxidase (rasburicase) was administered in a third group to assess the effect of lowering uric acid on outcomes. Other control groups include normal rats and hyperuricemic rats without cisplatin-induced injury. Cisplatin induced injury of the pars recta (S3) segment of the proximal tubule in association with a mild monocyte infiltration. Hyperuricemic rats showed significantly greater tubular injury and proliferation with significantly greater macrophage infiltration and increased expression of monocyte chemoattractant protein-1. However, renal function was not different between normouricemic and hyperuricemic rats with cisplatin injury. Treatment with rasburicase reversed the inflammatory changes and lessened tubular injury with an improvement in renal function (relative to the hyperuricemic group). No intrarenal crystals were observed in any groups. These data provide the first experimental evidence that uric acid, at concentrations that do not cause intrarenal crystal formation, may exacerbate renal injury in a model of acute renal failure. The mechanism may relate to a proinflammatory pathway involving chemokine expression with leukocyte infiltration.

scholarly journals Oridonin Attenuates Diabetes‑Induced Renal Fibrosis via Inhibition of the TXNIP/NLRP3 and NF‑κB Pathway in Rats

2021 ◽  
Author(s):  
Gengzhen Huang ◽  
Yaodan Zhang ◽  
Yingying Zhang ◽  
Xiaotao Zhou ◽  
Yuan Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Function ◽  
High Fat Diet ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Treated Group ◽  
Diabetic Rats ◽  
Inflammatory Factors ◽  
High Fat ◽  
Rabdosia Rubescens

Abstract Background: Oxidative stress and its induced inflammation are important pathological processes of diabetic nephropathy (DN). Oridonin, a component isolated from Rabdosia rubescens, possesses remarkable anti-inflammatory, immunoregulatory properties, it is also a newly reported NLRP3 inhibitor. However, the renoprotective effects of Oridonin and the underlying molecular mechanisms have not been explored in DN. We hypothesized that Oridonin could reduce NLRP3 pathway and ameliorate diabetes‑induced renal fibrosis.Methods: We used STZ-induced diabetic rats combined high-fat diet to establish a T2DM animal model, and then treated with Oridonin (10, 20 mg/kg/day) for two weeks. Kidney function and renal fibrosis were assessed. In addition, the expression of inflammatory factors and fibrotic markers were analyzed by western blot.Results: Oridonin treatment preserved kidney function and markedly limited the renal fibrosis size in diabetic rats. The renal fibrotic markers were inhibited in the 10 mg/kg/day group and 20 mg/kg/day group compared to the T2DM group. Moreover, the expression levels of TXNIP/NLRP3 and NF‑κB pathway were decreased in the Oridonin treatment group compared to non-treated group. Conclusions: The NLRP3-inflammasome inhibitor Oridonin reduces renal fibrosis and preserves kidney function in T2DM rat model, which indicates potential therapeutic effect of Oridonin on DN.

scholarly journals The Extract of Sonneratia apetala Leaves and Branches Ameliorates Hyperuricemia in Mice by Regulating Renal Uric Acid Transporters and Suppressing the Activation of the JAK/STAT Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu-Lin Wu ◽  
Jin-Fen Chen ◽  
Lin-Yun Jiang ◽  
Xiao-Li Wu ◽  
Yu-Hong Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Organic Anion ◽  
Janus Kinase ◽  
Vehicle Group ◽  
Cytokine Signaling ◽  
Sonneratia Apetala ◽  
Stat Signaling

Sonneratia apetala Buch-Ham., an exotic mangrove species with antidiabetic, antibacterial, and antioxidant capacities, mainly distributes in the southeast coastal areas in China. The present work investigated the protective effects of Sonneratia apetala leaves and branches extraction (SAL) on hyperuricemia (HUA) in mice. Potassium oxonate (PO) and hypoxanthine (HX) were used to establish the HUA model by challenge for consecutive 7 days. Results revealed that SAL inhibited the increases in kidney weight and index compared to the vehicle group. Meanwhile, SAL significantly decreased the levels of uric acid (UA), creatinine (CRE), and blood urea nitrogen (BUN) in serum. Additionally, SAL inhibited the activity of xanthine oxidase (XOD) in the liver. SAL ameliorated PO- and HX-induced histopathological changes. Moreover, it regulated oxidative stress markers including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) activity, and glutathione (GSH) content. Also, SAL inhibited the increases in renal levels of interleukin-6 (IL-6), interleukin-18 (IL-18), interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), monocyte chemotactic protein 1 (MCP-1), and transforming growth factor-β (TGF-β). SAL remarkably reduced suppressor of cytokine signaling 3 (SOCS3), Janus kinase 2 (JAK2), and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) expression. In addition, SAL inhibited the activation of nuclear factor kappa-B (NF-κB) in the kidney. Furthermore, SAL protected against HUA by regulating renal UA transporters of organic anion transporter (OAT1), urate reabsorption transporter 1 (URAT1), and glucose transporter 9 (GLUT9). These findings suggested that SAL ameliorated HUA by inhibiting the production of uric acid and enhancing renal urate excretion, which are related to oxidative stress and inflammation, and the possible molecular mechanisms include its ability to inhibit the JAK/STAT signaling pathway. Thus, SAL might be developed into a promising agent for HUA treatments.

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