Uric Acid Nephropathy: An Experimental Model

Stavrić, B.; Johnson, Willard J.; Grice, H. C.

doi:10.3181/00379727-130-33593

Cited by 39 publications

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“…1 By administering low doses of a uricase inhibitor, OA, in the diet, we were able to induce mild hyperuricemia (an increase of 1.5-to 2-fold in serum uric acid levels) and avoid previous models in which marked hyperuricemia occurs with intrarenal urate crystal deposition leading to acute renal failure. 9,10 Our primary finding was that an elevation in BP developed after 3 weeks of hyperuricemia. The difference in BPs between hyperuricemic and control animals was most marked in rats placed on a LS diet.…”

Section: Discussionmentioning

confidence: 97%

“…Kidney tissue from rats with acute uric acid nephropathy, induced by OA and uric acid administration, was used as a positive control. 9 Light microscopy was performed in 4-m sections of methyl Carnoy's fixed tissue stained with periodic acid-Schiff reagent. Methyl Carnoy's or formalin-fixed tissue sections were analyzed by indirect immunoperoxidase 11 staining with the following primary antibodies: OP199, a goat anti-mouse osteopontin (OPN; gift of C. Giachelli, University of Washington, Seattle); ED-1, a mouse anti-rat macrophage antibody (Serotec); goat anti-human type III collagen (Southern Biotechnology Associates Inc); mouse anti-human renin antibody (Sanofi Recherche); and rabbit anti-rat neuronal NO synthase (NOS1) (Transduction Laboratories).…”

Section: Renal Histologymentioning

confidence: 99%

“…Several previous groups had reported that hyperuricemia could be induced in rats by feeding them the uricase inhibitor oxonic acid (OA). 9 In most studies, uric acid supplements were also added to the diet, resulting in a 6-to 10-fold increase in serum uric acid levels with consequent marked uricosuria and acute renal failure secondary to obstruction of the renal tubules with urate crystals. 9 Targeted deletion of the uricase gene in mice also results in marked hyperuricemia, intrarenal urate crystal deposition, and renal failure.…”

mentioning

confidence: 99%

“…9 In most studies, uric acid supplements were also added to the diet, resulting in a 6-to 10-fold increase in serum uric acid levels with consequent marked uricosuria and acute renal failure secondary to obstruction of the renal tubules with urate crystals. 9 Targeted deletion of the uricase gene in mice also results in marked hyperuricemia, intrarenal urate crystal deposition, and renal failure. 10 Although these latter models mimic the acute urate nephropathy syndrome observed after chemotherapy in some patients with cancer (tumor lysis syndrome), they are inappropriate models for the mild hyperuricemia observed in patients with cardiovascular disease.…”

mentioning

confidence: 99%

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Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism

Mazzali¹,

Hughes²,

Kim³

et al. 2001

Hypertension

1,161

970

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Abstract-An elevation in circulating serum uric acid is strongly associated with the development of hypertension and renal disease, but whether uric acid has a causal role or whether it simply indicates patients at risk for these complications remains controversial. We tested the hypothesis that uric acid may have a causal role in the development of hypertension and renal disease by examining the effects of mild hyperuricemia in rats. Mild hyperuricemia was induced in rats by providing a uricase inhibitor (oxonic acid) in the diet. Hyperuricemic rats developed elevated blood pressure after 3 weeks, whereas control rats remained normotensive. The development of hypertension was prevented by concurrent treatment with either a xanthine oxidase inhibitor (allopurinol) or a uricosuric agent (benziodarone), both of which lowered uric acid levels. Blood pressure could also be lowered by reducing uric acid levels with either allopurinol or oxonic acid withdrawal. A direct relationship was found between blood pressure and uric acid (rϭ0.75, nϭ69), with a 10 -mm Hg blood pressure increase for each 0.03-mmol/L (0.5-mg/dL) incremental rise in serum uric acid. The kidneys were devoid of urate crystals and were normal by light microscopy. However, immunohistochemical stains documented an ischemic type of injury with collagen deposition, macrophage infiltration, and an increase in tubular expression of osteopontin. Hyperuricemic rats also exhibited an increase in juxtaglomerular renin and a decrease in macula densa neuronal NO synthase. Both the renal injury and hypertension were reduced by treatment with enalapril or L-arginine. In conclusion, mild hyperuricemia causes hypertension and renal injury in the rat via a crystal-independent mechanism, with stimulation of the renin-angiotensin system and inhibition of neuronal NO synthase. Key Words: uric acid Ⅲ hypertension, renal Ⅲ renin-angiotensin system Ⅲ nitric oxide U ric acid is a purine metabolite that in most mammals is degraded by the hepatic enzyme uricase to allantoin. However, mutations in the uricase gene occurred during primate development, with the consequence that humans have relatively higher levels of serum uric acid. 1 An elevation in serum uric acid has been associated with an increased risk for the development of hypertension, 2-4 and 25% to 50% of hypertensive individuals are hyperuricemic. 4 Hyperuricemia also confers increased risk for cardiovascular mortality, especially in women. 5,6 Despite the clinical and epidemiological evidence, many authorities do not consider an elevated uric acid to be a true cardiovascular risk factor, because patients with hyperuricemia often have other wellestablished risk factors for cardiovascular disease, such as hypertension, renal disease, obesity, dyslipidemia, and insulin resistance. 6 Several studies have found that an elevated uric acid level is an independent risk factor for cardiovascular disease after controlling for the contribution of established risk factors by multivariate analyses 2,3,7 ; however, other studies...

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Section: Discussionmentioning

confidence: 97%

Section: Renal Histologymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism

Mazzali¹,

Hughes²,

Kim³

et al. 2001

Hypertension

1,161

970

View full text Add to dashboard Cite

show abstract

“…Evidence from in vitro biochemical experiments and in vivo morphologic studies (9)(10)(11)(12)(13)(14)(15)(16) suggest that the renal shutdown is due to tubular obstruction from precipitation of excessive filtered and (or) secreted urate. However, some investigators have concluded that hyperuricemia per se may have acute nephrotoxic effects apart from the production of tubular uric acid deposits (15,17).…”

Section: Introductionmentioning

confidence: 99%

A micropuncture study of the early phase of acute urate nephropathy.

Conger¹,

Falk²,

Guggenheim³

et al. 1976

J. Clin. Invest.

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A B S T R A C T The early pathophysiological changes in acute urate nephropathy were investigated in a rat model using micropuncture, clearance, and morphologic methods. Plasma urate was increased from 1.2±0.6 to 20.1±3.1 mg/100 ml (P < 0.001). Urinary urate rose from 24.3±5.1 to 142.2±21.0 mg/100 ml (P <0.001).Renal plasma flow and glomerular filtration rate fell to 17 and 14% of control values, respectively, and urine flow rate decreased from 11.3±4.8 to 4.2±2.2 jdl/min (all P < 0.005) Superficial nephron filtration rate fell less than that of the whole kidney (70 vs. 86%). Both proximal and distal tubular pressures were increased from 10.6 to 26.1 mm Hg and from 7.2 to 24.7 mm Hg, respectively (P < 0.005). Efferent arteriolar and peritubular capillary pressures were increased twofold. Vascular resistance beyond the peritubular capillaries increased from 4.8 X 109 to 21.6 X 109 dynes s/cm5. Extensive deposits of uric acid and urate were found in the tubular system and vasa recti from the corticomedullary junction to the tip of the papilla.It is concluded from these experiments that not only tubular obstruction in the collecting ducts, but also obstruction of the distal renal vasculature, are the primary early pathogenetic events in acute urate nephropathy.

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Acute Uric Acid Nephropathy

Robinson¹,

Yarger²

1977

Arch Intern Med

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Uric Acid Nephropathy: An Experimental Model

Cited by 39 publications

References 0 publications

Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism

Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism

A micropuncture study of the early phase of acute urate nephropathy.

Acute Uric Acid Nephropathy

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