Uric acid has several reported effects by which it may cause DN illustrated in , including endothelial dysfunction, increased activity of the RAAS, and induction of inflammatory cascades, in addition to profibrotic cytokine activation all of which have been demonstrated to contribute to progression of microvascular disease and thereby renal injury in DN.
Mechanisms by which uric acid may cause diabetic nephropathy.
The effects of uric acid on the endothelium are subject of a contentious debate. On the one hand, uric acid has been shown to decrease nitric oxide (NO) production by endothelial cells in vitro
), and it does so in association with increased CRP expression (46
). Uric acid can also react with NO irreversibly leading to the formation of 6- aminouracil and may thus lead to NO depletion (47
). Furthermore, hyperuricemic rats develop endothelial dysfunction (as noted by reduced urinary nitrites), and if given early, L-arginine supplementation, can prevent both the systemic and glomerular hypertension in experimental hyperuricemia (48
). These data by our group and others suggest that uric acid leads to endothelial dysfunction. On the other hand however, some studies suggest that oxidative stress due to increased xanthine oxidase activity rather than uric acid is the major factor contributing to endothelial dysfunction. An example of such findings can be found in 2 double- blind placebo- controlled studies by George et al. (50
). Patients with congestive heart failure were randomized in the first study to allopurinol or placebo and in the second study to probenecid (a uricosuric agent) or placebo. Both treatment arms in both studies had lower serum uric acid levels, but endothelial function improved only in the study where allopurinol was administered. Direct comparisons between the allopurinol and the probenecid groups were not conducted in this study, hence, it remains unclear if the favorable outcomes noted with allopurinol treatment are secondary to xanthine oxidase inhibition, lowering uric acid, or perhaps both.
In the kidney, experimental hyperuricemia causes an afferent renal arteriolopathy and tubulointerstitial fibrosis. This effect is largely mediated by activating the RAAS, as the renal injury was reversed with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers but not with thiazide therapy despite all treatments lowering blood pressure (51
). In this study, uric acid was shown to induce vascular smooth muscle proliferation in vitro as well, and similar to the findings in the animal kidneys, the effects of uric acid on vascular smooth muscles was reversible with the use of losartan. In addition to a direct role for uric acid in the vasculature, such data suggest uric acid effects are mediated at least partially by activation of the RAAS.
On the inflammatory front, uric acid induces the interstitial inflammation and the local expression of chemokines such as MCP-1 in the kidney (52
), as well as COX-2 in the blood vessels (53
). A direct role for uric acid in inducing inflammation is further supported by the findings that when infused into mice, uric acid increases cytokine production (TNF-α) (54
). In humans with CKD, withdrawal of uric acid lowering therapy has been reported to increased urinary TGFβ-1 suggesting that hyperuricemia may contribute to the fibrotic process in patients with kidney disease (55
). In addition to stimulating TGF β-1 production, hyperuricemia may activate its downstream targets. Although the transcriptional effects of TGFβ-1 are generally mediated by a group of proteins; the Smads (56
), the expression of certain TGFβ-1-induced genes is mediated via the mitogen activate protein (MAP) kinase pathway (57
). This pathway has also been reported to mediate uric acid effects in cell culture (58
). Although the results of these studies need confirmation, such findings raise the possibility that treatment of hyperuricemia may provide a safe venue for alleviating cytokine- mediated kidney disease progression.