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Molecular Biological and Clinical Understanding of the Pathophysiology and Treatments of Hyperuricemia and Its Association with Metabolic Syndrome, Cardiovascular Diseases and Chronic Kidney Disease - PubMed

  • ️Fri Jan 01 2021

Review

Molecular Biological and Clinical Understanding of the Pathophysiology and Treatments of Hyperuricemia and Its Association with Metabolic Syndrome, Cardiovascular Diseases and Chronic Kidney Disease

Hidekatsu Yanai et al. Int J Mol Sci. 2021.

Abstract

Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from damaged, dying, and dead cells. The kidney plays a dominant role in UA excretion, and the kidney excretes approximately 70% of daily produced UA; the remaining 30% of UA is excreted from the intestine. When UA production exceeds UA excretion, hyperuricemia occurs. Hyperuricemia is significantly associated with the development and severity of the metabolic syndrome. The increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome. Hyperuricemia was previously thought to be simply the cause of gout and gouty arthritis. Further, the hyperuricemia observed in patients with renal diseases was considered to be caused by UA underexcretion due to renal failure, and was not considered as an aggressive treatment target. The evidences obtained by basic science suggests a pathogenic role of hyperuricemia in the development of chronic kidney disease (CKD) and cardiovascular diseases (CVD), by inducing inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells, and activation of the renin-angiotensin system. Further, clinical evidences suggest that hyperuricemia is associated with the development of CVD and CKD. Further, accumulated data suggested that the UA-lowering treatments slower the progression of such diseases.

Keywords: cardiovascular diseases; chronic kidney disease; hyperuricemia; uricosuric; xanthin oxidase.

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Conflict of interest statement

The authors declare no conflict of interest in relation to the present review paper.

Figures

Figure 1
Figure 1

Synthesis and excretion of UA. ABCG2, ATP-binding cassette, subfamily G, 2; AMP, adenosine monophosphate; APRT, adenine phosphoribosyltransferase; GMP, guanine monophosphate; GLUT9, glucose transporter 9; HPRT, hypoxanthine-guanine phosphoribosyltransferase; IMP, inosine monophosphate; OAT, organic anion transporter; PRPP, phosphor-ribosyl-pyrophosphate; PRS, phosphor-ribosyl-pyrophosphate synthetase; R-5-P, ribose-5-phosphate; UA, uric acid; URAT1, urate transporter 1; XO, xanthine oxidase.

Figure 2
Figure 2

Possible molecular mechanisms for the development of hyperuricemia in the metabolic syndrome. ABCG2, ATP-binding cassette, subfamily G, 2; ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; Fructose-1-P, fructose-1-phosphate; GAP3P, glyceraldehyde-3-phosphate; GA3PDH, glyceraldehyde-3-phosphate dehydrogenase; GMP, guanine monophosphate; GLUT9, glucose transporter 9; IMP, inosine monophosphate; PRPP, phosphor-ribosyl-pyrophosphate; PRS, phosphor-ribosyl-pyrophosphate synthetase; R-5-P, ribose-5-phosphate; UA, uric acid; URAT1, urate transporter 1; XO, xanthine oxidase.

Figure 3
Figure 3

The pharmacological action points of UA lowering treatments. AMP, adenosine monophosphate; GMP, guanine monophosphate; GLUT9, glucose transporter 9; IMP, inosine monophosphate; OAT4, organic anion transporter 4; PRPP, phosphor-ribosyl-pyrophosphate; PRS, phosphor-ribosyl-pyrophosphate synthetase; UA, uric acid; URAT1, urate transporter 1; XO, xanthine oxidase.

Figure 4
Figure 4

The UA lowering mechanism of non-UA-lowering drugs. AMP, adenosine monophosphate; GMP, guanine monophosphate; GLUT9, glucose transporter 9; IMP, inosine monophosphate; PRPP, phosphor-ribosyl-pyrophosphate; PRS, phosphor-ribosyl-pyrophosphate synthetase; SGLT2i, sodium-glucose cotransporter 2 inhibitors; UA, uric acid; URAT1, urate transporter 1; XO, xanthine oxidase.

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