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...

Macrophages have been proposed as a key cell type in the pathogenesis of renal fibrosis; however, the mechanism by which macrophages drive fibrosis is still unclear. We show that expression of galectin-3, a ␤-galactoside-binding lectin, is up-regulated in a mouse model of progressive renal fibrosis (unilateral ureteric obstruction, UUO), and absence of galectin-3 protects against renal myofibroblast accumulation/ activation and fibrosis. Furthermore, specific depletion of macrophages using CD11b-DTR mice reduces fibrosis severity after UUO demonstrating that macrophages are key cells in the pathogenesis of renal fibrosis. Disruption of the galectin-3 gene does not affect macrophage recruitment after UUO, or macrophage proinflammatory cytokine profiles in response to interferon-␥/lipopolysaccharide. In addition, absence of galectin-3 does not affect transforming growth factor-␤ expression or Smad 2/3 phosphorylation in obstructed kidneys. Adoptive transfer of wild-type but not galectin-3 ؊/؊ macrophages did, however, restore the fibrotic phenotype in galectin-3 ؊/؊ mice. Cross-over experiments using wild-type and galectin-3 ؊/؊ macrophage supernatants and renal fibroblasts confirmed that secretion of galectin-3 by macrophages is critical in the activation of renal fibroblasts to a profibrotic phenotype. Therefore, we demonstrate for the first time that galectin-3 expression and secretion by macrophages is a major mechanism linking macrophages to the promotion of renal fibrosis.

Increases in mesangial cell number may herald glomerular scarring, but they are not irreversible. This study sought mechanisms by which surplus glomerular mesangial cells can be cleared. A small proportion of cultured mesangial cells exhibited typical morphological features of apoptosis

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Individuals age >65 years old are the fastest expanding population demographic throughout the developed world. Consequently, more aged patients than before are receiving diagnoses of impaired renal function and nephrosclerosis-age-associated histologic changes in the kidneys. Recent studies have shown that the aged kidney undergoes a range of structural changes and has altered transcriptomic, hemodynamic, and physiologic behavior at rest and in response to renal insults. These changes impair the ability of the kidney to withstand and recover from injury, contributing to the high susceptibility of the aged population to AKI and their increased propensity to develop subsequent progressive CKD. In this review, we examine these features of the aged kidney and explore the various validated and putative pathways contributing to the changes observed with aging in both experimental animal models and humans. We also discuss the potential for additional study to increase understanding of the aged kidney and lead to novel therapeutic strategies.

The role played by resident macrophages (Mφ) in the initiation of peritoneal inflammation is currently unclear. We have used a conditional Mφ ablation strategy to determine the role of resident peritoneal Mφ in the regulation of neutrophil (PMN) recruitment in experimental peritonitis. We developed a novel conditional Mφ ablation transgenic mouse (designated CD11bDTR) based upon CD11b promoter-mediated expression of the human diphtheria toxin (DT) receptor. The murine DT receptor binds DT poorly such that expression of the human receptor confers toxin sensitivity. Intraperitoneal injection of minute (nanogram) doses of DT results in rapid and marked ablation of F4/80-positive Mφ populations in the peritoneum as well as the kidney, and ovary. In experimental peritonitis, resident Mφ ablation resulted in a dramatic attenuation of PMN infiltration that was rescued by the adoptive transfer of resident nontransgenic Mφ. Attenuation of PMN infiltration was associated with diminished CXC chemokine production at 1 h. These studies indicate a key role for resident peritoneal Mφ in sensing perturbation to the peritoneal microenvironment and regulating PMN infiltration.