Abstract
Crescentic glomerulonephritis (GN) is the most severe form of GN and is associated with significant morbidity and mortality despite aggressive immunotherapy with steroids, cytotoxic drugs, and plasmapheresis. We examined the therapeutic efficacy of the green tea polyphenol (−)-epigallocatechin-3-gallate (EGCG, 50 mg/kg BW/day x3weeks), a potent anti-inflammatory and anti-oxidant agent, on experimental crescentic GN induced in 129/svJ mice by administration of rabbit anti-mouse glomerular basement membrane sera. Routine histology and key molecules involved in inflammatory and redox signaling were studied. EGCG treatment significantly reduced mortality, decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. The improvements in renal function and histology were accompanied by the restoration of Nrf2 signaling (which was impaired in vehicle-treated mice) as shown by increased nuclear translocation of Nrf2 and cytoplasmic glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione peroxidase. EGCG-treated mice also showed reduction in p-Akt, p-JNK, p-ERK1/2 and p-P38 as well as restoration of PPARγ and SIRT1 levels. Lower dose of EGCG (25 mg/kg BW/day x2 weeks) treatment also significantly decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. Thus, our data illustrate the efficacy of EGCG in reversing the progression of crescentic GN in mice by targeting multiple signaling and inflammatory pathways as well as countering oxidative stress.
Highlights
Crescentic glomerulonephritis (GN) includes a variety of conditions characterized by glomerular fibrinoid necrosis and accumulation of cells in Bowman’s space
The EGCG-treated mice showed significantly less proteinuria and lower serum creatinine than the vehicle-treated mice (Table 1). These findings demonstrated that EGCG administration improved renal function and reduced mortality in mice with established anti-glomerular basement membrane (GBM) GN
We have previously shown that glomerular disease in the mouse model of anti-GBM-GN is accompanied by oxidative damage as shown by increased levels of malondialdehyde and H2O2, upregulation of myeloperoxidase and NADPH oxidase, downregulation of catalase and glutathione peroxidase, increased levels of nitrotyrosine, activation of NFkB, upregulation of inducible nitric oxide synthase and osteopontin expression, and decreased PPARγ expression [17]
Summary
Crescentic glomerulonephritis (GN) includes a variety of conditions characterized by glomerular fibrinoid necrosis and accumulation of cells in Bowman’s space It can be classified into three categories: pauci-immune, immune complex-mediated, and anti-glomerular basement membrane (GBM) antibody-induced crescentic GN (anti-GBM-GN) [1,2]. Anti-GBM-GN is pathologically and clinically the most severe form of GN with end-stage renal disease developing in 40–70% of the affected patients [1,2]. It is caused by an inflammatory reaction in the glomerular capillaries initiated by circulating antibodies directed to the GBM components, noncollagenous-1 (NC1) domain of the α3 or α5 chain of type IV collagen [1,3,4]. The nonspecific nature of these therapeutic regimes and frequently disabling side effects beg for an urgent development of new and more targeted therapeutic strategies [5]
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