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Inhibition of macrophage migration inhibitory factor reduces diabetic nephropathy in type II diabetes mice
Zhigang Wang1, Meng Wei, Meng Wang
1School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Abstract:
Macrophage migration inhibitory factor (MIF) plays a critical role in inflammation and is elevated in diabetic kidney. However, whether MIF plays a causative role in diabetic nephropathy (DN) remains unclear. In the present study, we have demonstrated that after treatment of 8-week-old diabetic db/db and nondiabetic db/m mice with the MIF inhibitor ISO-1 (20 mg/kg) for 8 weeks, there was a significant decrease in blood glucose, albuminuria, extracellular matrix accumulation, epithelial-mesenchymal transition (EMT), and macrophage activation in the kidney of db/db mice. Incubation of macrophages with MIF induced the production of proinflammatory cytokines, including interleukin (IL) 6, IL-1β, tumor necrosis factor α (TNF-α). The conditioned media (CM) of MIF-activated macrophages and TNF-α induced by MIF caused podocyte damage. Moreover, CM from MIF-activated macrophages induced EMT of renal tubular cells, and this effect was blocked by ISO-1. Thus, MIF inhibition may be a potential therapeutic strategy for DN. This effect may be attributable to its inhibitory effect on macrophage activation in the diabetic kidney.
Insights
Macrophage migration inhibitory factor (MIF) drives diabetic kidney disease progression. Inhibiting MIF with ISO-1 reduced inflammation, glucose, and kidney damage in diabetic mice, suggesting a new therapeutic approach.
Area of Science:
- Nephrology
- Immunology
- Endocrinology
Background:
- Macrophage migration inhibitory factor (MIF) is implicated in inflammation and elevated in diabetic kidneys.
- The specific role of MIF in the development of diabetic nephropathy (DN) is not fully understood.
Purpose of the Study:
- To investigate the causative role of MIF in diabetic nephropathy (DN).
- To evaluate the therapeutic potential of a MIF inhibitor, ISO-1, in a mouse model of DN.
Main Methods:
- Diabetic (db/db) and non-diabetic (db/m) mice were treated with the MIF inhibitor ISO-1 for 8 weeks.
- Key markers of kidney damage, inflammation, and cellular changes were assessed.
- In vitro studies examined the effects of MIF on macrophages and renal cells.
Main Results:
- ISO-1 treatment significantly reduced blood glucose, albuminuria, and extracellular matrix accumulation in diabetic mice.
- MIF inhibition decreased macrophage activation and inflammatory cytokine production (IL-6, IL-1β, TNF-α) in the kidney.
- MIF-activated macrophages induced podocyte damage and renal tubular cell epithelial-mesenchymal transition (EMT), effects blocked by ISO-1.
Conclusions:
- MIF inhibition with ISO-1 ameliorates key pathological features of diabetic nephropathy in mice.
- MIF plays a causative role in DN progression, potentially through macrophage activation and induction of EMT.
- Targeting MIF represents a promising therapeutic strategy for managing diabetic kidney disease.
