Moderate hyperuricaemia ameliorated kidney damage in a low-renin model of experimental renal insufficiency

Abstract

Uric acid has promoted renal fibrosis and inflammation in experimental studies, but some studies have shown nephroprotective effects due to alleviated oxidative stress. We studied the influence of experimental hyperuricaemia in surgically 5/6 nephrectomized rats. Three weeks after subtotal nephrectomy or sham operation, the rats were allocated to control diet or 2.0% oxonic acid (uricase inhibitor) diet for 9 weeks. Then blood, urine and tissue samples were taken, and renal morphology and oxidative stress were examined. Inflammation and fibrosis were evaluated using immunohistochemistry and real-time PCR (RT-PCR). Remnant kidney rats ingesting normal or oxonic acid diet presented with ~60% reduction of creatinine clearance and suppressed plasma renin activity. Oxonic acid diet increased plasma uric acid levels by >80 μmol/L. In remnant kidney rats, moderate hyperuricaemia decreased glomerulosclerosis, tubulointerstitial damage and kidney mast cell count, without influencing the fibrosis marker collagen I messenger RNA (mRNA) content. In both sham-operated and 5/6 nephrectomized rats, the mast cell product 11-epi-prostaglandin-F_2α excretion to the urine and kidney tissue cyclooxygenase-2 (COX-2) levels were decreased. To conclude, hyperuricaemic remnant kidney rats displayed improved kidney morphology and reduced markers of oxidative stress and inflammation. Thus, moderately elevated plasma uric acid had beneficial effects on the kidney in this low-renin model of experimental renal insufficiency.

Keywords: experimental renal insufficiency; hyperuricaemia; kidney morphology; oxonic acid.

FIGURE 1

Urinary protein excretion during study week 12 (A), kidney arteriosclerosis index (B), glomerulosclerosis index (C), tubulointerstitial damage index (D), correlation between urinary protein excretion and glomerulosclerosis score (E) and representative photomicrograph of smooth muscle actin (SMA) staining of the glomerular arterioles (F) in the study groups (n = 11–12 in each group). NX, 5/6 nephrectomized rat; Oxo, 2.0% oxonic acid diet; Sham, sham‐operated rat. Values are median (thick line), 25th–75th percentile (box) and range (whiskers), and outliers are depicted as small circles. *P < 0.05 versus Sham. ^† P < 0.05 versus NX

FIGURE 2

The 24‐h urinary excretion of 11‐epi‐prostaglandin F_2α during study week 3 (A) and study week 12 (B), kidney haem oxygenase‐1 (HO‐1) mRNA expression (C) and kidney mast cell content (D) in the study groups (n = 12 in each group). Groups as in Figure 1. Values are mean ± S.E.M., median (thick line), 25th–75th percentile (box) and range (whiskers), and outliers are depicted as small circles. *P < 0.05 versus Sham. ^† P < 0.05 versus NX

FIGURE 3

Representative photomicrographs of the immunohistochemical staining of glomerular (A) and tubulointerstitial (B) cyclooxygenase‐2 (COX‐2), tubulointerstitial COX‐2 score (C) and number of COX‐2‐positive cells in the glomeruli (D) in the study groups (n = 9–11 in each group). Groups as in Figure 1. Values are mean ± S.E.M. *P < 0.05 versus Sham. ^† P < 0.05 versus NX