Podocyte Injury and Albuminuria in Experimental Hyperuricemic Model Rats

Abstract

Although hyperuricemia is shown to accelerate chronic kidney disease, the mechanisms remain unclear. Accumulating studies also indicate that uric acid has both pro- and antioxidant properties. We postulated that hyperuricemia impairs the function of glomerular podocytes, resulting in albuminuria. Hyperuricemic model was induced by oral administration of 2% oxonic acid, a uricase inhibitor. Oxonic acid caused a twofold increase in serum uric acid levels at 8 weeks when compared to control animals. Hyperuricemia in this model was associated with the increase in blood pressure and the wall-thickening of afferent arterioles as well as arcuate arteries. Notably, hyperuricemic rats showed significant albuminuria, and the podocyte injury marker, desmin, was upregulated in the glomeruli. Conversely, podocin, the key component of podocyte slit diaphragm, was downregulated. Structural analysis using transmission electron microscopy confirmed podocyte injury in this model. We found that urinary 8-hydroxy-2′-deoxyguanosine levels were significantly increased and correlated with albuminuria and podocytopathy. Interestingly, although the superoxide dismutase mimetic, tempol, ameliorated the vascular changes and the hypertension, it failed to reduce albuminuria, suggesting that vascular remodeling and podocyte injury in this model are mediated through different mechanisms. In conclusion, vasculopathy and podocytopathy may distinctly contribute to the kidney injury in a hyperuricemic state.

Renoprotective effect of topiroxostat via antioxidant activity in puromycin aminonucleoside nephrosis rats

“…This finding is analogous to our recent report by increasing serum UA by administration uricase inhibitor oxonic acid in the rats in which XO activity was downregulated by increase in intracellular UA (Asakawa et al. ). We need to elucidate the molecular mechanism on the linkage between cell UA and NOX4 activation in the future.…”

“…The result showed that UA in the medium clearly increased NOX4 expression, suggesting that increased UA within the cell may be causative in increasing NOX4 expression independently of XO activity. This finding is analogous to our recent report by increasing serum UA by administration uricase inhibitor oxonic acid in the rats in which XO activity was downregulated by increase in intracellular UA (Asakawa et al 2017). We need to elucidate the molecular mechanism on the linkage between cell UA and NOX4 activation in the future.…”

“…This rapid response clearly showed that NOX4 expression is a downstream phenomenon of the increase in UA and independently of XO activity because hyperuricemia rather downregulates the XO activity as shown in the kidney cortex taken from the oxonic acid‐induced hyperuricemic model rats (Asakawa et al. ).…”

“…The preparation for transmission electron microscopy (TEM) was performed according to standard procedures as described previously (Asakawa et al. ). The tissue blocks were fixed in 2.5% glutaraldehyde and embedded in Epon.…”

Research Advances in the Mechanisms of Hyperuricemia-Induced Renal Injury

“…Electron microscopy of kidney biopsies from patients with gout revealed varying degrees of podocyte proliferation and damage [ 78 ]. Signs of significant albuminuria were found in hyperuricemic model rats, accompanied by upregulation of desmin, a podocyte injury marker, and downregulation of podocin, a key component of the podocyte slit diaphragm [ 79 , 80 ].…”