Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: A review

Abstract

The association between uric acid (UA) on one side and systemic hypertension (Htn), dyslipidemia, glucose intolerance, overweight, fatty liver, renal disease and cardiovascular disease (CVD) on the other side is well recognized. However, the causal relationship between UA and these different clinical problems is still debatable. The recent years have witnessed hundreds of experimental and clinical trials that favored the opinion that UA is a probable player in the pathogenesis of these disease entities. These studies disclosed the strong association between hyperuricemia and metabolic syndrome (MS), obesity, Htn, type 2 diabetes mellitus (DM), non-alcoholic fatty liver disease, hypertriglyceridemia, acute kidney injury, chronic kidney disease (CKD), coronary heart disease (CHD), heart failure and increased mortality among cardiac and CKD patients. The association between UA and nephrolithiasis or preeclampsia is a non-debatable association. Recent experimental trials have disclosed different changes in enzyme activities induced by UA. Nitric oxide (NO) synthase, adenosine monophosphate kinase (AMPK), adenosine monophosphate dehydrogenase (AMPD), and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase are affected by UA. These changes in enzymatic activities can lead to the observed biochemical and pathological changes associated with UA. The recent experimental, clinical, interventional, and epidemiologic trials favor the concept of a causative role of UA in the pathogenesis of MS, renal, and CVDs.

Keywords: Acute kidney injury; Cardiovascular disease; Chronic kidney disease; Insulin resistance; Non-alcoholic fatty liver disease; Uric acid.

Graphical abstract

Fig. 1

Effect of intra-cellular uric acid on nitric oxide synthesis within vascular endothelium UA = uric acid; NO = nitric oxide; FMD = flow mediated dilation; Htn = systemic hypertension.

Fig. 2

Intra-cellular uric acid stimulates gluconeogenesis. UA = uric acid; AMPD = adenosine monophosphate dehydrogenase; AMPK = adenosine monophosphate protein kinase.

Fig. 3

Uric acid as mediator of systemic hypertension. ENaC = epithelial sodium channels; Na = sodium; HTn = systemic hypertension.

Fig. 4

Pathways of lipogenesis activated by intra-cellular uric acid. UA = uric acid; AMPD = adenosine monophosphate dehydrogenase; AMPK = adenosine monophosphate protein kinase; ROS = reactive oxygen species; ER = endoplasmic reticulum.

Fig. 5

Intracellular uric acid as a pro-oxidant agent. UA = uric acid; ROS = reactive oxygen species.

Fig. 6

Different pathogenic mechanisms of kidney injury possibly induced by uric acid. UA = uric acid; ROS = reactive oxygen species; MCPl = Macrophage chemo-attractant protein-1; RAS = renin angiotensin system; EMT = epithelium mesenchyme transition; VSMC = vascular smooth muscle cells.

Fig. 7

Different vascular injury mechanisms possibly mediated by uric acid. UA – uric acid; ROS = reactive oxygen species l; RAS = renin angiotensin system; PDGFR – platelet derived growth factor receptor.