Single Nucleotide Polymorphisms in the Melanocortin His-Phe-Arg-Trp Sequences Decrease Tetrapeptide Potency and Efficacy

Winget, Marshall D.; Ericson, Mark D.; Freeman, Katie T.; Haskell‐Luevano, Carrie

doi:10.1021/acsmedchemlett.9b00198

Cited by 4 publications

(3 citation statements)

References 32 publications

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“…Therefore, it is possible that the potential effect of NDP-MSH on systemic or renal hemodynamics may cause glomerular hyperperfusion and thereby counteract the anti-proteinuric action secondary to podocyte protection. Another explanation is that NDP-MSH or α-MSH, despite being claimed to be a pan-MCR agonist, does not have equal agonistic activities on all MCRs, but has the greatest activating activity on MC1R that is about 25 times greater than the MC5R agonistic activity ( Winget et al, 2020 ). Thus, it is possible that at the dose of NDP-MSH used in our animals, MC1R rather than MC5R was fully activated.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Melanocortin 5 Receptor Activation Attenuates Glomerular Injury and Proteinuria in Rats With Puromycin Aminonucleoside Nephrosis

Chen

Alam

et al. 2022

Front. Physiol.

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Clinical evidence indicates that the melanocortin peptide ACTH is effective in inducing remission of nephrotic glomerulopathies like minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), including those resistant to steroids. This suggests that a steroid-independent melancortinergic mechanism may contribute. However, the type of melanocortin receptor (MCR) that conveys this beneficial effect as well as the underlying mechanisms remain controversial. Burgeoning evidence suggests that MC5R is expressed in glomeruli and may be involved in glomerular pathobiology. This study aims to test the effectiveness of a novel highly selective MC5R agonist (MC5R-A) in puromycin aminonucleoside (PAN) nephrosis. Upon PAN injury, rats developed evident proteinuria on day 5, denoting an established nephrotic glomerulopathy. Following vehicle treatment, proteinuria continued to persist on day 14 with prominent histologic signs of podocytopathy, marked by ultrastructural glomerular lesions, including extensive podocyte foot process effacement. Concomitantly, there was loss of podocyte homeostatic markers, such as synaptopodin and podocin, and de novo expression of the podocyte injury marker desmin. Treatment with MC5R-A attenuated urine protein excretion and mitigated the loss of podocyte marker proteins, resulting in improved podocyte ultrastructural changes. In vitro in cultured podocytes, MC5R-A prevented the PAN-induced disruption of actin cytoskeleton integrity and apoptosis. MC5R-A treatment in PAN-injured podocytes also reinstated inhibitory phosphorylation and thus averted hyperactivity of GSK3β, a convergent point of multiple podocytopathic pathways. Collectively, pharmacologic activation of MC5R by using the highly selective small-molecule agonist is likely a promising therapeutic strategy to improve proteinuria and glomerular injury in protenuric nephropathies.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Melanocortin 5 Receptor Activation Attenuates Glomerular Injury and Proteinuria in Rats With Puromycin Aminonucleoside Nephrosis

Chen

Alam

et al. 2022

Front. Physiol.

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“…Melanocortins are produced by POMC neurons in the pars intermedia of the pituitary gland, the hypothalamic arcuate nucleus and the dorsal medullary nucleus of the solitary tract. They can be distinguished by the presence of an invariant amino acid sequence in each melanocortin peptide, His-Phe-Arg-Trp [3]. The melanocortins produced in humans include alpha-melanocyte stimulating hormone (α-MSH), beta-melanocyte stimulating hormone (β-MSH), gamma-melanocyte stimulating hormone (γ-MSH) and adrenocorticotropic hormone (ACTH).…”

Section: Melanocortins and The Pomc Systemmentioning

confidence: 99%

Melanocortins and Their Potential for the Treatment, Prevention and Amelioration of Complications of Diabetes

Robinson,

Pickering

2024

Diabetology

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Diabetes mellitus (type I and II) is an advancing global health problem, concerningly increasing in prevalence in most of the developed and developing world. Current therapies, such as the subcutaneous injection of insulin, are invasive and require a close monitoring of blood glucose levels to prevent hypo- or hyperglycaemia from occurring. Despite an inexorable search for a cure since Banting and Best discovered and purified insulin in 1921, insulin remains a solitary insula, still the gold standard for treatment of type I and late-stage type II diabetes mellitus. Apropos of complications, diabetes causes a myriad of secondary maladies, ranging from diabetic kidney disease, diabetic retinopathy and diabetic neuropathy to erectile dysfunction and peripheral vascular disease. While scientists continue to interminably tinker with perfecting mechanical insulin pumps or dampening the immune response to pancreatic beta cells, an important aspect of the aetiology of diabetes should not be neglected, that of the metabolism. At its heart, diabetes can arguably be considered a metabolic disease, and this review suggests a return to focusing on preventing and treating diabetes by focussing on its metabolic causes. This narrative review summarises the potential of a recent class of synthetic peptides, the melanocortins, to help prevent and treat the complications of diabetes mellitus. The review summarises recent work showing the potential benefits of the melanocortins in treating diabetic complications through various pathways.

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“…β-MSH, β-LPH, γ-LPH, and β-Endorphin are processed from the carboxy-terminal region of POMC [ 13 ]. Each of the melanocortin ligands shares the conserved sequence of His-Phe-Arg-Trp (HFRW), which functions as a pharmacophore for MCR signaling [ 14 , 15 ].…”

Section: Melanocortinsmentioning

confidence: 99%

Antifibrotic and Anti-Inflammatory Actions of α-Melanocytic Hormone: New Roles for an Old Player

Dinparastisaleh

Mirsaeidi

2021

Pharmaceuticals

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The melanocortin system encompasses melanocortin peptides, five receptors, and two endogenous antagonists. Besides pigmentary effects generated by α-Melanocytic Hormone (α-MSH), new physiologic roles in sexual activity, exocrine secretion, energy homeostasis, as well as immunomodulatory actions, exerted by melanocortins, have been described recently. Among the most common and burdensome consequences of chronic inflammation is the development of fibrosis. Depending on the regenerative capacity of the affected tissue and the quality of the inflammatory response, the outcome is not always perfect, with the development of some fibrosis. Despite the heterogeneous etiology and clinical presentations, fibrosis in many pathological states follows the same path of activation or migration of fibroblasts, and the differentiation of fibroblasts to myofibroblasts, which produce collagen and α-SMA in fibrosing tissue. The melanocortin agonists might have favorable effects on the trajectories leading from tissue injury to inflammation, from inflammation to fibrosis, and from fibrosis to organ dysfunction. In this review we briefly summarized the data on structure, receptor signaling, and anti-inflammatory and anti-fibrotic properties of α-MSH and proposed that α-MSH analogues might be promising future therapeutic candidates for inflammatory and fibrotic diseases, regarding their favorable safety profile.

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Single Nucleotide Polymorphisms in the Melanocortin His-Phe-Arg-Trp Sequences Decrease Tetrapeptide Potency and Efficacy

Cited by 4 publications

References 32 publications

Pharmacological Melanocortin 5 Receptor Activation Attenuates Glomerular Injury and Proteinuria in Rats With Puromycin Aminonucleoside Nephrosis

Pharmacological Melanocortin 5 Receptor Activation Attenuates Glomerular Injury and Proteinuria in Rats With Puromycin Aminonucleoside Nephrosis

Melanocortins and Their Potential for the Treatment, Prevention and Amelioration of Complications of Diabetes

Antifibrotic and Anti-Inflammatory Actions of α-Melanocytic Hormone: New Roles for an Old Player

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