Amplification of the Melanocortin-1 Receptor in Nephrotic Syndrome Identifies a Target for Podocyte Cytoskeleton Stabilization

Bergwall, Lovisa; Wallentin, Hanna; Elvin, Johannes; Liu, Peidi; Boi, Roberto; Sihlbom, Carina; Hayes, Kyle; Wright, Dale; Haraldsson, Börje; Nyström, Jenny; Buvall, Lisa

doi:10.1038/s41598-018-34004-7

Cited by 16 publications

(10 citation statements)

References 33 publications

(48 reference statements)

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“…In addition, Acthar Gel has activity at MC1R, which is present on neutrophils, monocytes, macrophages, dendritic cells, and B lymphocytes and reduces inflammation [5,13]. MC1R in podocytes has been implicated in providing renoprotective effects in patients with nephrotic syndrome through stabilization of the actin cytoskeleton, and Acthar Gel has been shown to have such renoprotective effects in a rodent model of focal segmental glomerulosclerosis [31,44]. Interestingly, Acthar Gel appeared to be a partial agonist at MC5R, which is expressed on a variety of immune cells, including Table 4.…”

Section: Discussionmentioning

confidence: 99%

Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists

Huang

Galen

Zweifel

et al. 2020

Journal of Receptors and Signal Transduction

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Purpose: To compare the binding and agonistic activity of Acthar V R Gel and synthetic melanocortin receptor (MCR) agonists and examine how the activity of select agonists affects the in vivo production of corticosterone. Materials and Methods: In vitro binding was determined using concentration-dependent displacement of the ligand [ 125 I]Nle 4 , D-Phe 7-a-melanocyte-stimulating hormone (a-MSH) on cells expressing MC1R, MC3R, MC4R, or MC5R. Functional activity was determined using a time-resolved fluorescence cyclic adenosine monophosphate (cAMP) assay in cells expressing MC1R, MC2R, MC3R, MC4R, or MC5R. In vivo corticosterone analyses were performed by measuring plasma corticosterone levels in Sprague Dawley rats. Results: Acthar Gel and synthetic MCR agonists exhibited the highest binding at MC1R, lowest binding at MC5R, and moderate binding at MC3R and MC4R. Acthar Gel stimulated the production of cAMP in all 5 MCR-expressing cell lines, with MC2R displaying the lowest level of full agonist activity, 3-, 6.6-, and 10-fold lower than MC1R, MC3R, and MC4R, respectively. Acthar Gel was a partial agonist at MC5R. The synthetic MCR agonists induced full activity at all 5 MCRs, with the exception of a-MSH having no activity at MC2R. Acthar Gel treatment had less of an impact on in vivo production of corticosterone compared with synthetic ACTH 1-24 depot. Conclusions: Acthar Gel bound to and activated each MCR tested in this study, with partial agonist activity at MC5R and the lowest level of full agonist activity at MC2R, which distinguished it from synthetic MCR agonists. The minimal activity of Acthar Gel at MC2R corresponded to lower endogenous corticosteroid production.

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Section: Discussionmentioning

confidence: 99%

Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists

Huang

Galen

Zweifel

et al. 2020

Journal of Receptors and Signal Transduction

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“…Autonomic and neuroendocrine functions appear to be heavily regulated by MC4R [17], whereas MC1R, MC3R, and MC5R are involved in steroid-independent immunomodulation of immune cells [18]. Increasing evidence suggests that MC1R activation alone may serve as a podocyte-specific target in kidney injury [19][20][21][22].…”

Section: Repository Corticotropin Injectionmentioning

confidence: 99%

Repository corticotropin injection versus corticosteroids for protection against renal damage in a focal segmental glomerulosclerosis rodent model

et al. 2020

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Background Focal segmental glomerulosclerosis (FSGS) causes renal fibrosis and may lead to kidney failure. FSGS and its common complication, proteinuria, are challenging to treat. Corticosteroids are ineffective in many patients with FSGS, and alternative treatments often yield suboptimal responses. Repository corticotropin injection (RCI; Acthar® Gel), a naturally sourced complex mixture of purified adrenocorticotropic hormone analogs and other pituitary peptides, may have beneficial effects on idiopathic FSGS via melanocortin receptor activation. Methods Two studies in a preclinical (female Sprague-Dawley rats) puromycin aminonucleoside FSGS model assessed the effect of RCI on renal function and morphology: an 8-week comparison of a single RCI dose with methylprednisolone (N = 27), and a 12-week chronic RCI dose range study (N = 34). Primary outcomes were proteinuria and renal pathology improvements for measures of renal fibrosis, tubular damage, glomerular injury, and total kidney injury score. Impact of RCI treatment was also determined by assessing urinary biomarkers for renal injury, podocyte expression of podoplanin (a biomarker for injury), podocyte effacement by electron microscopy, and histological staining for fibrosis biomarkers. Results Compared with saline treatment, RCI 30 IU/kg significantly reduced proteinuria, with a 38% reduction in peak mean urine protein levels on day 28 in the 8-week model, and RCI 10 IU/kg, 30 IU/kg, and 60 IU/kg reduced peak mean urine protein in the 12-week model by 18, 47, and 44%, respectively. RCI also showed significant dose-dependent improvements in fibrosis, interstitial inflammation, tubular injury, and glomerular changes. Total kidney injury score (calculated from histopathological evaluations) demonstrated statistically significant improvements with RCI 30 IU/kg in the 8-week study and RCI 60 IU/kg in the 12-week study. RCI treatment improved levels of urinary biomarkers of kidney injury (KIM-1 and OPN), expression of podoplanin, and podocyte morphology. RCI also reduced levels of desmin and fibrosis-associated collagen deposition staining. Methylprednisolone did not improve renal function or pathology in this model. Conclusions These results provide evidence supporting the improvement of FSGS with RCI, which was superior to corticosteroid treatment in this experimental model. To the authors’ knowledge, this is the first evidence that a drug for the treatment of FSGS supports podocyte recovery after repeated injury.

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“…The PAN nephrosis model involves not only glomerular cytotoxicity but also immune dysregulation. In support of this, TNF-α can directly trigger glomerular injury in rats ( Taylor and Namba, 2001 ) and its production by monocytes collected from animals with PAN injury was found to be elevated ( Bertani et al, 1989 ; Gómez-Chiarri et al, 1994 ). In addition, macrophage-derived foam cells are present in diseased glomeruli in the PAN models ( Magil and Cohen, 1989 ).…”

Section: Discussionmentioning

confidence: 93%

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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Amplification of the Melanocortin-1 Receptor in Nephrotic Syndrome Identifies a Target for Podocyte Cytoskeleton Stabilization

Cited by 16 publications

References 33 publications

Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists

Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists

Repository corticotropin injection versus corticosteroids for protection against renal damage in a focal segmental glomerulosclerosis rodent model

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

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