title: A role for uric acid in the progression of renal disease.
abstract: 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 inhibitor. 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.
authors.affiliation: Division of Nephrology, Baylor College of Medicine, Houston, Texas, USA. dhkang@ewha.ac.kr
authors.forename: Duk-Hee
authors.initials: DH
authors.lastname: Kang
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Lili
authors.initials: L
authors.lastname: Feng
authors.forename: Susumu
authors.initials: S
authors.lastname: Watanabe
authors.forename: Lin
authors.initials: L
authors.lastname: Han
authors.forename: Marilda
authors.initials: M
authors.lastname: Mazzali
authors.forename: Luan
authors.initials: L
authors.lastname: Truong
authors.forename: Raymond
authors.initials: R
authors.lastname: Harris
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2; D018450:Disease Progression; D006973:Hypertension / Q000209:etiology; D006984:Hypertrophy; D033461:Hyperuricemia / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000150:complications / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009392:Nephrectomy / Q000379:methods; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D012084:Renin-Angiotensin System / Q000502:physiology; D014527:Uric Acid / Q000378:metabolism* / Q000494:pharmacology; D014652:Vascular Diseases / Q000209:etiology
chemical_list: D007527:Isoenzymes; D014527:Uric Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases