Lipoic acid does not improve renal function markers in 5/6 nephrectomy model: possible role of Nrf2 inactivation

Abstract

Chronic kidney disease (CKD) progression and complications are associated with increased oxidative stress, as well as with Nrf2 inactivation. Lipoic acid (LA) has been considered an inducer of Nrf2 antioxidant response. We tested whether oral administration of LA provides beneficial effects in experimental CKD in rats. Wistar rats underwent 5/6 nephrectomy (CKD group) or sham laparotomy. Seven days later, CKD group was divided into three subgroups that received: (i) LA continuously in the drinking water (100 mg/kg/day), (ii) LA by gavage every other day (100 mg/kg), or (iii) no LA treatment. LA treatment lasted until day 60. Plasma urea and creatinine, 24 hproteinuria, glomerulosclerosis, interstitial fibrosis/tubular atrophy, and Nrf2 activation were analyzed. All parameters measured were significantly altered in the untreated CKD group, compared with the sham group, as expected. Oral LA administration, either in the drinking water or by gavage, did not improve significantly any parameter, comparing the treated-groups with the untreated CKD group. These results indicate that oral LA administration for 53 days was ineffective to reactivate Nrf2 in the remnant kidney of uremic rats, likely preventing improvements in biochemical and histopathological markers of renal function. ARTICLE HISTORY

Renal-Protective Roles of Lipoic Acid in Kidney Disease

“…Another potential mechanism of ALA’s nephroprotection in diabetes is its ability to activate the Nrf2 signaling pathway, leading to upregulation of the second-phase cytoprotective proteins such as heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) [ 56 , 57 , 58 ]. It should be pointed out that while ALA is nephroprotective in diabetic kidney disease, it may impose pro-oxidant or toxic effects and could fail to serve as an Nrf2 inducer under certain pathophysiological conditions [ 59 , 60 , 61 ]. Additionally, while ALA has been thought to activate insulin signaling pathways to combat diabetes [ 28 ] and has been shown to prevent high fructose-induced cardiometabolic disorders and renal dysfunction [ 62 ], it has also been reported that ALA could only attenuate proteinuria and oxidative stress without slowing progression of diabetic renal failure [ 63 ].…”