The renaissance of corticotropin therapy in proteinuric nephropathies

Abstract

Refractory nephrotic syndrome continues to be a therapeutic challenge despite advances in immunosuppression and blockade of the renin-angiotensin-aldosterone cascade. Adrenocorticotropic hormone (ACTH), a pituitary neuroimmunoendocrine polypeptide, was widely used in the 1950s as an effective therapy for childhood nephrotic syndrome, but has since been replaced by synthetic glucocorticoid analogues. In addition to controlling steroidogenesis, ACTH also acts as an important physiological agonist of the melanocortin system. Clinical and experimental evidence now suggests that ACTH has antiproteinuric, lipid-lowering and renoprotective properties, which are not fully explained by its steroidogenic effects. ACTH therapy is effective in inducing remission of nephrotic syndrome in patients with a variety of proteinuric nephropathies, even those resistant to steroids and other immunosuppressants. This Perspectives article describes the biophysiology of ACTH, with an emphasis on its melanocortin actions, particularly in renal parenchymal cells, which could potentially explain the therapeutic effects of ACTH in nephrotic glomerulopathies.

Figure 1

Biosynthesis of ACTH and its regulation by the hypothalamic–pituitary–adrenal axis. a | ACTH is one of several physiologically active peptides that are biosynthesized from the precursor peptide pre-POMC by corticotrophs in the anterior lobe of the pituitary gland. POMC undergoes a series of post-translational modifications before it is proteolytically cleaved by prohormone convertase enzymes to yield a chemically and biogenetically related family of polypeptides with varying physiological activity, including ACTH and other natural melanocortins (blue), like α- MSH, β-MSH, γ-MSH, and LPH as well as CLIP. b | Stress induces synthesis and release of ACTH from corticotrophs in the anterior lobe of the pituitary gland through various hormones, including corticotropin-releasing hormone and arginine vasopressin, which are secreted by the hypothalamus. ACTH synthesis and release are controlled by slow, intermediate or fast negative feedback at multiple levels by multiple substances secreted within the HPA axis, including cortisol, which is released from the adrenal cortex following ACTH-mediated activation of the melanocortin 2 receptor (MC2R) on adrenocortical cells. Abbreviations: ACTH, adrenocorticotropic hormone; CLIP, corticotrophin-like intermediate peptide; HPA, hypothalamic–pituitary–adrenal; LPH, lipotropic hormone; MSH, melanocyte-stimulating hormone; POMC, pro-opiomelanocortin.

Figure 2

Expression of melanocortin receptors in podocytes. a | In frozen sections of rat kidney, immunofluorescent staining for MCR (green) is colocalized with a podocyte marker (red), and demonstrates perfect superposition of these markers in a merged image (yellow). Nuclear counterstaining was obtained with DAPI (blue). b | In cultured murine podocytes, immunofluorescent staining for MCR reveals a punctate, cytoplasmic membrane distribution of this receptor (green). Abbreviations: 4,6 diamidino 2 phenylindole; MCR, melanocortin receptor.

Figure 3

Potential mechanisms underlying the therapeutic efficacy of ACTH in proteinuric nephropathies. ACTH could induce remission of proteinuria and exert renoprotective effects through a variety of potential mechanisms, including (but not limited to): corticosteroid-mediated systemic immunosuppression and anti-inflammatory actions in the kidney subsequent to ACTH-induced steroidogenesis; direct MCR-mediated systemic immunomodulation and anti-inflammatory effects; direct MCR-mediated protective effects on kidney cells, particularly podocytes; kidney protection secondary to correction of dyslipidemia mediated by MCR on hepatic cells; and renal protection via neurogenic anti-inflammatory effects mediated by MCRs expressed in the central nervous system. Abbreviations: ACTH, adrenocorticotropic hormone; APC, antigen-presenting cells; GFR, glomerular filtration rate; Lp(a), lipoprotein (a); MCR, melanocortin receptor; NK, natural killer.