Melanocortin System in Kidney Homeostasis and Disease: Novel Therapeutic Opportunities

Abstract

Melanocortin peptides, melanocortin receptors, melanocortin receptor accessory proteins, and endogenous antagonists of melanocortin receptors are the key components constituting the melanocortin hormone system, one of the most complex and important hormonal systems in our body. A plethora of evidence suggests that melanocortins possess a protective activity in a variety of kidney diseases in both rodent models and human patients. In particular, the steroidogenic melanocortin peptide adrenocorticotropic hormone (ACTH), has been shown to exert a beneficial effect in a number of kidney diseases, possibly via a mechanism independent of its steroidogenic activity. In patients with steroid-resistant nephrotic glomerulopathy, ACTH monotherapy is still effective in inducing proteinuria remission. This has inspired research on potential implications of the melanocortin system in glomerular diseases. However, our understanding of the role of the melanocortinergic pathway in kidney disease is very limited, and there are still huge unknowns to be explored. The most controversial among these is the identification of effector cells in the kidney as well as the melanocortin receptors responsible for conveying the renoprotective action. This review article introduces the melanocortin hormone system, summarizes the existing evidence for the expression of melanocortin receptors in the kidney, and evaluates the potential strategy of melanocortin therapy for kidney disease.

Identification of Endothelial Cell Protein C Receptor by Urinary Proteomics as Novel Prognostic Marker in Non-Recovery Kidney Injury

“…In this case, IRE-1 would stimulate the JNK pathway, which regulates cell death/survival and downstream proinflammatory cytokines to promote the inflammation [ 15 ]. The precursor protein, pro-opiomelanocortin (POMC), gives rise to melanocortin peptides (ACTH, α-MSH, β-MSH, and γ-MSH) that are important for dealing with ER stress during AKI [ 16 ]. ACTH ameliorates the severity of kidney injury in animal models [ 17 ].…”

Negative Modulation of B Cell Activation by Melanocortin 1 Receptor Signaling Protects against Membranous Nephropathy

“…Beneficial effects of melanocortin therapy have been reported in both clinical and experimental MN. 6,46 MC1R-mediated signaling has been posited to mediate this protective activity because treatment with a selective MC1R agonist was sufficient to protect against experimental MN. 15,47 In further support of this hypothesis, our data here demonstrate that MC1R KO worsens PHN in rats and blunts the benefit of melanocortin therapy.…”

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

“…Although they provide a sustained weight loss (up to 15% average of total body weight in long-term large-scale trials), according to studies, 70% of patients taking GLP-1 agonists discontinue use after 24 months (it is still a matter of speculation as to why this is so, but some have postulated that severe nausea and other gastrointestinal side effects could be major contributors, as well as cost and ease-of-access issues) [58][59][60]. Melanocortins can cause skin darkening, flushing, increased libido, spontaneous erections and mild nausea but are generally well-tolerated, some of these side effects may be seen as additional benefits (although they may not be desirable for all people), hence the colloquial moniker of the melanocortin class as being "Barbie drugs" as they cause skin tanning, weight loss and sexual arousal [61,62]. Spurred on by weight loss results seen in healthy obese women using the FDA-approved female sexual dysfunction melanocortin drug bremelanotide (an average loss of 1.3 kg bodyweight over 16 days and a reduction of an average of 400 kcal in food consumption per day in the first phase I trial and an average loss of 1.7 kg bodyweight over 12 days in the second phase I trial; side effects in the trial were classed as mostly mild, whilst a smaller subset of subjects had side effects classed as moderate; skin darkening was reported as a side effect in 15-63.3% of the bremelanotide-treated group across both studies; and five patients had to withdraw due to nausea, dizziness and hypertension), Palatin Pharmaceuticals is developing a combination treatment of bremelanotide and a low-dose GLP-1 agonist to treat obesity [52].…”

“…Chronic kidney disease (CKD) is the irreversible alteration of kidney structure and function over an extended period of time [77]. Diabetic nephropathy is the main cause of CKD, comprising up to 30-50% of all CKD, a condition without a definitive cure [61,77]. Very few studies to date have looked at the melanocortins in diabetic nephropathy despite the need for new therapeutics for CKD.…”

“…Corticosteroids are commonly used in the treatment of kidney disease; however, patients can have side effects including an increased risk of developing diabetes mellitus [79]. ACTH was later found to have steroid-independent effects through binding to the MC3R and a superior side effect profile [61,80]. ACTH treatment improved proteinuria and glomerular filtration rate in patients with membranous glomerular nephropathy [81].…”