Braden Sims

Introduction. Improper management of Diabetes Mellitus (DM) can lead to the progression of Diabetic Nephropathy (DN), which is the leading cause of end-stage kidney disease in most developed countries, including the United States.¹ Progression of DN and worsening renal function have been strongly associated with the interplay and overactivation of proinflammatory innate immune cells and the Renin-Angiotensin System (RAS).^2,3 Tumor Necrosis Factor α (TNF- α) is a cytokine that is known to be both overexpressed during pathogenic activation of RAS and play a role in the recruitment and polarization of M1 macrophages.⁴ Researchers have speculated that progression of DN can be controlled by regulating circulating levels of TNF- α. Methods. Peer-reviewed publications were used to investigate the interplay between the RAS, TNF- α and macrophages in DN progression. In the first experiment, patients with Type II DM were given two anticoagulative medications that preserve blood flow (Beraprost sodium (BPS) and Alprostadil) to both prevent RAS activation and reduce TNF- α production.⁵ In the second experiment, an anti-TNF-α antibody was given to diabetic mice to observe the cytokine’s impacted on the progression of DN.⁴ In the third experiment, an antagonist to CCR2 (a potent macrophage chemoattractant) was given to diabetic mice to observe its impact on macrophage recruitment and production of TNF- α.⁶ Results. The patients treated with BPS and Alprostadil had statistically significantly lower RAS products (renin and angiotensin II) and TNF- α levels when compared to the control group, which was associated with preserved renal function.⁵ Diabetic mice that were treated with an anti-TNF-α antibody experienced significantly reduced glomerular macrophage recruitment, improved kidney function, preserved normal nephron structures and reduced the levels of the circulating cytokines granulocyte-macrophage colony-stimulating factor, TNF-α and MCP-1.⁴ Treatment with the CCR2 antagonist lead to statistically significant decreases in circulating TNF- α levels and macrophage recruitment while increasing renal function.⁶ Conclusions. Preventing RAS overactivation and decreasing levels of TNF- α slows the progression of DN by preventing the recruitment, polarization, and anti-inflammatory actions of M1 macrophages.

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