Spinach Extract Reduces Kidney Damage in Diabetic Rats by Impairing the AGEs/RAGE Axis.

The interaction between advanced glycation end products (AGEs) and their RAGE receptor (AGEs/RAGE axis) triggers several signaling pathways that lead to the development of diabetic nephropathy (DN). One of the most studied AGEs is Nε-(1-Carboxymethyl)-L-lysine (CML). Spinacia oleracea is an edible plant with beneficial health properties, but its effect on the AGE/RAGE axis in kidney damage is unknown. OBJECTIVE: We aimed to investigate the functional role of spinach methanolic extract (SME) on kidney damage in diabetic rats associated with the CML/RAGE axis. METHODS: Forty adult male Wistar rats were used in this study and divided into four groups: control rats (CTRL), SME-administered CTRL (400 mg/kg; SME), streptozotocin-induced diabetic nephropathy rats (STZ), and SME-treated STZ (STZ-SME); treatments were administered daily. After 12 weeks, serum AGEs, creatinine in urine, and lipid peroxidation in kidneys were measured. The distribution and expression levels of inflammatory and fibrotic mediators and RAGE signaling were evaluated through immunohistochemistry (NOX4, CML, RAGE, nuclear NF-κB, TNF-α, IL-1β, TGF-β1, SMAD2/3, CTGF, and a-SMA) and immunolocalization of CML/RAGE. RESULTS: Glycoside flavonoid derivatives, such as patuletin and spinacetin, were primarily identified in the extract. Kidneys from the STZ group showed altered morphology, dead cells in the proximal tubules, and increased oxidative stress markers; notably, these effects were improved by SME treatment (STZ-SME). The STZ-SME group showed a lower staining intensity for CML and RAGE, which was associated with a decrease in the expression of inflammatory and fibrotic factors compared with the STZ group. In all groups, the distribution of these markers varied among proximal tubule, glomerular, and interstitial cells. CONCLUSIONS: SME treatment may help to prevent or delay kidney damage in diabetic rats by regulating inflammatory and fibrotic processes associated with the AGEs/RAGE pathway, a mechanism involved in the development of nephropathy.