Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 ± 2.5 versus 17.5 ± 3.4%; P < 0.05) and interstitial fibrosis (1.89 ± 0.45 versus 1.52 ± 0.47; P < 0.05). Hyperuricemic rats developed vascular disease consisting of thickening of the preglomerular arteries with smooth muscle cell proliferation; these changes were significantly more severe than a historical RK group with similar BP. Allopurinol significantly reduced uric acid levels and blocked the renal functional and histologic changes. Benziodarone reduced uric acid levels less effectively and only partially improved BP and renal function, with minimal effect on the vascular changes. To better understand the mechanism for the vascular disease, the expression of COX-2 and renin were examined. Hyperuricemic rats showed increased renal renin and COX-2 expression, the latter especially in preglomerular arterial vessels. In in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhihbitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.

Recent experimental and human studies have shown that hyperuricemia is associated with hypertension, systemic inflammation, and cardiovascular disease mediated by endothelial dysfunction and pathologic vascular remodeling. Elevated levels of C-reactive protein (CRP) have emerged as one of the most powerful independent predictors of cardiovascular disease. In addition to being a marker of inflammation, recent evidence suggests that CRP may participate directly in the development of atherosclerotic vascular disease. For investigating whether uric acid (UA)-induced inflammatory reaction and vascular remodeling is related to CRP, the UA-induced expression of CRP in human vascular smooth muscle cells (HVSMC) and human umbilical vein endothelial cells (HUVEC) was examined, as well as the pathogenetic role of CRP in vascular remodeling. It is interesting that HVSMC and HUVEC expressed CRP mRNA and protein constitutively, revealing that vascular cells are another source of CRP production. UA (6 to 12 mg/dl) upregulated CRP mRNA expression in HVSMC and HUVEC with a concomitant increase in CRP release into cell culture media. Inhibition of p38 or extracellular signal–regulated kinase 44/42 significantly suppressed UA-induced CRP expression, implicating these pathways in the response to UA. UA stimulated HVSMC proliferation whereas UA inhibited serum-induced proliferation of HUVEC assessed by ³H-thymidine uptake and cell counting, which was attenuated by co-incubation with probenecid, the organic anion transport inhibitor, suggesting that entry of UA into cells is responsible for CRP expression. UA also increased HVSMC migration and inhibited HUVEC migration. In HUVEC, UA reduced nitric oxide (NO) release. Treatment of vascular cells with anti-CRP antibody revealed a reversal of the effect of UA on cell proliferation and migration in HVSMC and NO release in HUVEC, which suggests that CRP expression may be responsible for UA-induced vascular remodeling. This is the first study to show that soluble UA, at physiologic concentrations, has profound effects on human vascular cells. The observation that UA alters the proliferation/migration and NO release of human vascular cells, mediated by the expression of CRP, calls for careful reconsideration of the role of UA in hypertension and vascular disease.

Summary: Background and objectives: Recent data suggest indoxyl sulfate (IS), one of the uremic toxins that accelerate the progression of chronic kidney disease (CKD), may also be responsible for vascular disease via an induction of oxidative stress. The role of IS in endothelial dysfunction in CKD and potential mechanisms of IS-induced endothelial dysfunction were investigated. Design, setting, participants, & measurements: A prospective observational study in 40 CKD patients was performed. Flow-mediated endothelium-dependent vasodilatation (FMD) and its reaction time before and 24 weeks after an oral adsorbent of IS were evaluated. Plasma levels of IS and markers of oxidative stress were also measured. The proliferation, senescence, and production of nitric oxide and reactive oxygen species from human umbilical vein endothelial cells (HUVEC) were evaluated and the effect of antioxidants, N-acetylcysteine, rotenone, and apocynin was examined to explore the mechanism of IS-induced endothelial dysfunction. Results: AST-120 treatment for 24 weeks resulted in a significant increase in FMD with a decrease in IS and oxidized/reduced glutathione ratio. The presence of diabetes and high-sensitivity C-reactive protein were the independent predictors for an improved FMD. IS induced a production of reactive oxygen species in HUVEC, and pretreatment with antioxidants ameliorated IS-induced inhibition of proliferation and nitric oxide production and inhibited a senescence of HUVEC. Conclusions: IS may play an important role in endothelial dysfunction via generation of oxidative stress with an induction of endothelial senescence. AST-120 improved endothelial dysfunction in patients with CKD associated with a decrease in IS and a restoration of antioxidant reserve.

Kang DH, et al. Electrolyte Blood Press. 2014 Jun;12(1):1-6. http://dx.doi.org/10.5049/EBP.2014.12.1.1

Over time, peritoneal dialysis results in functional and structural alterations of the peritoneal membrane, but the underlying mechanisms and whether these changes are reversible are not completely understood. Here, we studied the effects of high levels of glucose, which are found in the dialysate, on human peritoneal mesothelial cells (HPMCs). We found that high concentrations of glucose induced epithelial-to-mesenchymal transition (EMT) of HPMC, suggested by decreased expression of E-cadherin and increased expression of α-smooth muscle actin, fibronectin, and type I collagen and by increased cell migration. Normalization of glucose concentration on day 2 reversed the phenotypic transformation, but the changes were irreversible after 7 d of stimulation with high glucose. In addition, exposure of HPMC to high glucose resulted in a decreased expression of the antifibrotic cytokines, hepatocyte growth factor (HGF) and bone morphogenic protein 7 (BMP-7). Exogenous treatment with HGF resulted in a dosage-dependent prevention of high glucose–induced EMT. Both BMP-7 peptide and gene transfection with an adenoviral vector of BMP-7 also protected HPMCs from EMT. Furthermore, adenoviral BMP-7 transfection decreased peritoneal EMT and ameliorated peritoneal thickening in an animal model of peritoneal dialysis. In summary, high concentrations of glucose induce a reversible EMT of HPMCs, associated with decreased production of HGF and BMP-7. Treatment of HPMCs with HGF or BMP-7 blocks high glucose–induced EMT, and BMP-7 ameliorates peritoneal fibrosis in an animal model of peritoneal dialysis.