Malate Ameliorates Unilateral Ureter Obstruction (UUO)‐Induced Nephropathy Through Stimulation of Nuclear Factor Erythroid‐2 (Nrf2) and its Related Genes

Abstract

The Tricarboxylic acid cycle (TCA) is central to the production of metabolic energy needed in the cardiorenal system. Lately, the activity of fumarase, an enzyme in the TCA cycle which hydrates fumarate to malate, has conferred additional blood pressure regulatory function to TCA cycle products. Hence, there is a tendency that the TCA cycle products could mitigate hypertension-related pathologies such as acute kidney injury (AKI) and eventual chronic kidney injury (CKD). This study aimed to evaluate the effect of the TCA cycle product, malate in UUO, a model which provides an overlap between AKI and CKD. Kidney injury was induced in anaesthetized rats via surgical ligation of the left ureter. The rats were then treated with malate (600 mg/kg p.o.) for 10 days. Western blot and biochemical analyses were carried out on homogenized kidney fractions after treatment. There were no changes in proteinuria and sodium excretion in UUO rats treated with malate (P>0.05). Malate increased arginase activity the cortex (0.4±0.1 vs 2.2±0.1 µM/µg, P<0.01) and medulla (1.7±0.0 vs 2.7±0.1 µM/µg, P<0.01) of UUO rats. Consistent with this, Nitric oxide production was unchanged in malate-treated-UUO rats. Nrf2 expression was significantly increased in the cortex (59 %, P<0.01) of malate-treated UUO rats. However, there was a tendency for an increased expression in the medulla. Although, superoxide dismutase (SOD) activity was not significantly different in the cortex and medulla of UUO rats treated with malate (P>0.05), there was a time-dependent increase (P<0.05) in catalase (CAT) in the cortex but not medulla of malate-treated UUO rats. On the contrary, malate worsened TGF-β expression (38 %, P<0.01) in the cortex but not medulla of UUO rats. Also, collagenase activity was consistently increased in the cortex (88.4±2.3 vs 128.2±11.6 µM/mg, p<0.01) and reduced in the medulla (149.6±6.1 vs 131.6±4.2 µM/mg, P<0.05) of UUO rats treated with malate. In addition, Kidney injury molecule (KIM-1) expression was significantly reduced in the medulla (43 %, P<0.05) of UUO rats treated with malate. In conclusion, malate had no effect on fibrosis but ameliorated the inflammation and slowed progressive tubular damage associated with UUO nephropathy via activation of antioxidant response products and affiliated genes.