Safranal Ameliorates Renal Damage, Inflammation, and Podocyte Injury in Membranous Nephropathy via SIRT/NF-κB Signalling

Objective: Safranal is a natural product from saffron (Crocus sativus L.) with anti-inflammatory and nephroprotective potential. This study aimed to explore the role of safranal in a cationic bovine serum albumin (C-BSA)-induced rat model of membranous glomerulonephritis (MGN).

Methods: After model establishment, Sprague-Dawley rats were administered 100 or 200 mg/kg safranal by gavage. A biochemical analyser was used to measure the urine protein levels and serum levels of renal function parameters. Hematoxylin-eosin and immunofluorescence staining of kidney tissues were performed to examine histopathological changes and assess the expression of IgG, C3, and SIRT1. Western blotting was performed to measure the protein levels of podocin, nephrin, SIRT1, and factors involved in the NF-κB/p65 pathway. Inflammatory cytokine levels in renal homogenates were determined by ELISA.

Results: Safranal at 100 or 200 mg/kg reduced kidney weight (2.07 ± 0.15 g and 2.05 ± 0.15 g) and the kidney somatic index (0.83 ± 0.08% and 0.81 ± 0.08%) in MGN rats compared with those in the model group without drug administration (2.62 ± 0.17 g and 1.05 ± 0.1%). C-BSA increased the urine protein level to 117.68 ± 10.52 mg/day (compared with the sham group, 5.03 ± 0.45 mg/day), caused dysregulation of renal function indicators, and induced glomerular expansion and inflammatory cell infiltration in the rat kidney samples. All the biochemical and histological changes were improved by safranal administration. Safranal at two doses also increased the fluorescence intensities of IgG (0.1 ± 0.009 and 0.088 ± 0.008) and C3 (0.065 ± 0.006 and 0.048 ± 0.004) compared with those in the MGN group (0.15 ± 0.013 and 0.086 ± 0.008). Additionally, safranal reversed the downregulation of podocin, nephrin, and Wilms tumor protein-1 (WT1) levels and reversed the high inflammatory cytokine levels in MGN rats. Mechanistically, safranal activated SIRT1 signalling to interfere with NF-κB signalling in the kidney tissues of MGN rats.

Conclusions: Safranal ameliorates renal damage, inflammation, and podocyte injury in MGN by upregulating SIRT1 and inhibiting NF-κB signalling.

Inflammation; Membranous nephropathy; Nuclear factor kappa B; Safranal; Sirtuin type-1.