Inflammation and oxidative stress are hallmarks and mediators of the progression of CKD.
Bardoxolone methyl, a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated
antioxidant and anti-inflammatory response, increases estimated GFR and decreases BUN, serum
phosphorus, and
uric acid concentrations in patients with moderate to severe CKD. However, it also increases
albuminuria, which is associated with
inflammation and
disease progression. Therefore, we investigated whether this
bardoxolone methyl-induced
albuminuria may result from the downregulation of
megalin, a
protein involved in the tubular reabsorption of
albumin and
lipid-bound
proteins. Administration of
bardoxolone methyl to cynomolgus monkeys significantly decreased the
protein expression of renal tubular
megalin, which inversely correlated with the urine
albumin-to-
creatinine ratio. Moreover, daily
oral administration of
bardoxolone methyl to monkeys for 1 year did not lead to any adverse effects on renal histopathologic findings but did reduce serum
creatinine and BUN, as observed in patients with CKD. Finally, the
bardoxolone methyl-induced decrease in
megalin corresponded with pharmacologic induction of renal Nrf2 targets, including
NAD(P)H:
quinone oxidoreductase 1
enzyme activity and
glutathione content. This result indicates that Nrf2 may have a role in
megalin regulation. In conclusion, these data suggest that the increase in
albuminuria that accompanies
bardoxolone methyl administration may result, at least in part, from reduced expression of
megalin, which seems to occur without adverse effects and with strong induction of Nrf2 targets.