Effect of lowering uric acid on renal disease in the type 2 diabeticdb/dbmice

Abstract

Hyperuricemia has recently been recognized to be a risk factor for nephropathy in the diabetic subject. We tested the hypothesis that lowering uric acid with a xanthine oxidase inhibitor might reduce renal injury in the diabetic mouse. Diabetic (db/db) mice were treated with allopurinol or no treatment for 8 wk. Serum uric acid, renal function, and histology were assessed at death. The direct effect of uric acid in human proximal tubular epithelial cells was also evaluated under normal or high glucose condition. We found that db/db mice developed hyperuricemia, albuminuria, mesangial matrix expansion, and mild tubulointerstitial disease. Allopurinol treatment significantly lowered uric acid levels, reduced albuminuria, and ameliorated tubulointerstitial injury, but it did not prevent mesangial expansion. The mechanism for protection was shown to be due to a reduction in inflammatory cells mediated by a reduction in ICAM-1 expression by tubular epithelial cells. Interestingly, allopurinol did not reduce oxidative stress in the kidney. An inflammatory role of uric acid on tubular cells was also confirmed by our in vitro evidence that uric acid directly induced ICAM-1 expression in the human proximal tubular cell. In conclusion, hyperuricemia has a pathogenic role in the mild tubulointerstitial injury associated with diabetic nephropathy but not glomerular damage in db/db mice. Lowering uric acid may reduce tubulointerstitial injury in diabetes.

Predictors of diabetic nephropathy

“…Results showed that diabetic mice had higher mean serum uric acid compared to controls (P < 0.05) [54]. Diabetic mice receiving allopurinol showed significantly reduced uric acid levels (P < 0.001), decreased albuminuria (P <0.05) and attenuated tubulointerstitial damage (P < 0.01), though mesangial expansion persisted reflecting glomerular damage [54]. The mechanism of protection of allopurinol was found to be through decreased epithelial cell expression of InterCellular Adhesion Molecule-1 (ICAM-1).…”

“…Intrigued with such relationship, it was crucial to investigate the exact mechanisms underlying SUA and if using xanthine oxidase inhibitors might decrease kidney injury in diabetic mice [54]. For eight weeks, mice were divided into 4 groups with 10 mice per group; group 1: control mice, group 2: control mice receiving allopurinol, group 3: diabetic mice and group 4: diabetic mice receiving allopurinol [54].…”

“…For eight weeks, mice were divided into 4 groups with 10 mice per group; group 1: control mice, group 2: control mice receiving allopurinol, group 3: diabetic mice and group 4: diabetic mice receiving allopurinol [54]. Results showed that diabetic mice had higher mean serum uric acid compared to controls (P < 0.05) [54].…”

“…For eight weeks, mice were divided into 4 groups with 10 mice per group; group 1: control mice, group 2: control mice receiving allopurinol, group 3: diabetic mice and group 4: diabetic mice receiving allopurinol [54]. Results showed that diabetic mice had higher mean serum uric acid compared to controls (P < 0.05) [54]. Diabetic mice receiving allopurinol showed significantly reduced uric acid levels (P < 0.001), decreased albuminuria (P <0.05) and attenuated tubulointerstitial damage (P < 0.01), though mesangial expansion persisted reflecting glomerular damage [54].…”

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

“…The extent of the mesangial expansion was determined by assessing the PAS-positive and nuclei-free area in the mesangium on 30 glomeruli of six mice in each group using ScanScope image analyzer (Aperio Technologies, Vista, CA). 78 Immunohistochemistry Formalin-fixed tissues were deparaffinized, rehydrated, and processed for antigen retrieval using 10 mM citrate buffer (pH 6.0) for VEGF (Millipore, Billerica, MA). The sections were incubated with primary antibody overnight at 4°C, followed by treatment with peroxidasecoupled secondary antibody.…”