Leveraging Melanocortin Pathways to Treat Glomerular Diseases

Abstract

The melanocortin system is a neuroimmunoendocrine hormone system that constitutes the fulcrum in the homeostatic control of a diverse array of physiological functions, including melanogenesis, inflammation, immunomodulation, adrenocortical steroidogenesis, hemodynamics, natriuresis, energy homeostasis, sexual function and exocrine secretion. The kidney is a quintessential effector organ of the melanocortin hormone system with melanocortin receptors abundantly expressed by multiple renal paranchymal cells, including podocytes, mesangial cells, glomerular endothelial cells and renal tubular cells. Converging evidence unequivocally demonstrates that the melanocortin based therapy by using the melanocortin peptide adrenocorticotropic hormone (ACTH) is prominently effective in inducing remission of steroid resistant nephrotic syndrome caused by a variety of glomerular diseases, including membranous nephropathy and podocytopathies such as minimal change disease and focal segmental glomerulosclerosis, suggesting a steroidogenic independent melanocortin mechanism. Mechanistically, ACTH and other melanocortin peptides as well as synthetic melanocortin analogues possess potent proteinuria reducing and renoprotective effects that could be attributable to both direct protection of glomerular cells and systemic immunomodulation. Thus, leveraging melanocortin signaling pathways by using either the existing U.S. Food and Drug Administration approved melanocorin peptide ACTH or novel synthetic melanocortin analogues represents a promising and pragmatic therapeutic strategy for glomerular diseases. This review article introduces the biophysiology of melanocortin hormone system with emphasis on the kidney as the target organ, discusses the existing clinical and experimental data on melanocortin treatments for glomerular diseases, elucidates the potential mechanisms of action, and describes the potential side effects of melanocortin based therapy.

Relapse of Nephrotic Syndrome after Adrenocorticotropic Hormone-Induced Remission: Implications of Adrenocorticotropic Hormone Antibodies

“…Corticotropin or ACTH has been successfully used in the treatment of nephrotic syndrome since 1950s. In the past, it was believed that the antiproteinuric effect of ACTH may be attributed to its steroidogenic activity through a direct action on the melanocortin 2 receptor [3,11] on the adrenal cortex. However, recently more and more studies suggest that ACTH is still quite effective in patients with steroid-resistant glomerular diseases, denoting a steroidogenic-independent proteinurea-reducing activity of ACTH [2].…”

“…It is hypothesized that the antiproteinuric action of ACTH is not solely attributed to its steroidogenic effects because a number of case series studies found that patients with steroid-resistant nephrotic syndrome still respond well to ACTH therapy [2]. Increasing evidence suggests that ACTH may exert a glomerular protective and antiproteinuric effect via multipronged mechanisms, including direct podocyte protection, lipid lowering action, and potent melanocortinergic activities [3].…”

Idiopathic Membranous Nephropathy: Diagnostic and Therapeutic Challenges

“…In addition to this steroidogenic mechanism, there is growing evidence that some renoprotective and antiproteinuric consequences of ACTH are related to steroid-independent melanocortin effects on extra-adrenal tissue, including the kidneys. These nonsteroidal results include anti-inflammatory, anti-apoptotic, and immunomodulatory effects that are important in treating glomerular disease [32,33] . These mechanisms could help explain the therapeutic benefit of ACTH for our patient without producing significant immunosuppression and activating his underlying infections.…”

Targeting Regulatory T Cells for Transplant Tolerance: New Insights and Future Perspectives

“…Systemic administration of GSK3β inhibitor resulted in prolonged islet survival in an allotransplant mouse model, suggesting that GSK3β could be a promising therapeutic target to increase the stability and function of Tregs for inducing allotransplant tolerance [33]. Inhibition of GSK3β could be achieved by a number of cytokines, growth factors, and humoral factors in humans [34], including some neuropeptides like melanocortins and adrenocorticotropic hormone [35][36][37][38]. In support of this, treatment of primed T cells with the melanocortin peptide α-melanocyte-stimulating hormone (α-MSH) could induce tolerance/anergy in primed CD4 + T-helper cells and mediate induction of CD25 + CD4 + Tregs through an MC5R-dependent mechanism, thus resulting in tolerance to experimental autoimmune injuries [39][40][41].…”