Therapeutic Effects And Mechanisms Of Melanocortin In Focal Segmental Glomerulosclerosis

Background and objectiveAdrenocorticotropic hormone(ACTH),a melanocortin-like drug,may be effective in children with focal segmental glomerulosclerosis(FSGS)who are resistant to first-line hormone therapy,and may play an important role in reducing urinary protein,protecting renal function and delaying the progression of renal disease in children with FSGS.The melanocortin 2 receptor(MCR2)is mainly located in the adrenal glands and is thought to be the only receptor with a high affinity for ACTH that does not bind to other melanocyte stimulating hormones(MSH)such as α,β and y-MSH.MCR2 mainly mediates glucocorticoid production.In children with hormone-resistant FSGS,ACTH treatment is effective,suggesting that ACTH has a dual role in promoting glucocorticoid production via MCR2 and in binding to other melanocortin receptors(MCRs)to exert its non-steroidal therapeutic effects.The mechanism of action of the latter is not fully understood.In this study,we reported the data of 2 children with FSGS who applied ACTH clinically in our department,and analyzed the literature that previously reported the efficacy of applying ACTH to treat FSGS.We further gave NDP-MSH,an analogue of α-MSH,to intervene in FSGS model mice,and observed and compared the blood TH17 and Treg cell levels,urinary protein,urinary creatinine and renal inflammatory factor expression and pathological manifestations of mice in the drug intervention group with those in the model group to clarify the non-steroidal therapeutic effects and mechanisms of corticotropin on FSGS.Methods1.Clinical study:The data of 2 children with FSGS treated with ACTH from the Department of Pediatrics of the First Affiliated Hospital of Zhengzhou University from January 2017 to December 2019 were selected,using the Chinese keywords"corticotropin" or "adrenocorticotropic hormone" and "focal segmental glomerulosclerosis",respectively.The keywords "focal segmental glomerulosclerosis","Adrenocorticotropic hormone" and"focal segmental glomerulosclerosis" were used as search terms,and the cases of ACTH treatment for FSGS reported at home and abroad were searched in China Knowledge Network Database(CNKI),Wanfang Database,Vipshop Database,Pubmed Database,Geenmedical Database,Web of Science Database,etc.,and combined with the literature review,the cases of ACTH treatment for FSGS were analyzed.literature review to comprehensively analyze the therapeutic effect of ACTH on FSGS.2.Animal experiments:(1)72 healthy male C57b1/6 mice,weighing 20-25 g at 8 weeks of age,were randomly divided into intervention group(24 mice),model group(24 mice)and control group(24 mice)..(2)Mice modeling:The mice in the intervention group and the model group(48 mice)were injected with 25 mg/kg of adriamycin in the tail vein to construct the FSGS model,and the control group was injected with the same amount of saline.The mice in the intervention group were injected with NDP-MSH 1mg/kg subcutaneously 6h before and every other day after the modeling,and the model was injected with the same amount of saline subcutaneously.(3)6 mice were randomly selected from each group on day 7,day 14,day 21 and day 28 to collect 24-hour urine,blood and kidney tissues.24-hour urine specimens were used to determine total urine protein and urine creatinine,blood was used to detect Th17 and Treg cell levels,and kidney tissue specimens were fixed,sectioned and stained for light and electron microscopic examination,and IL-6,IL-17,IL-18,and IL-18 were measured in kidney tissues.IL-17,IL-18,TNF-α,PCX expression in kidney tissues were measured.(4)Observe and compare the levels of Th17 and Treg cells in the blood,total protein and creatinine in the urine of each group of mice at different time points,and observe the morphology of kidney tissues and compare the levels of IL-6,IL-17,IL-18,TNF-α and PCX expressed in kidney tissues at different time points.Results1 Clinical studies In this study,complete remission was achieved in 2 children with FSGS who applied ACTH.A total of 127 patients with FSGS treated with ACTH were retrieved from the literature,19 achieved complete remission and 42 achieved partial remission.2 Animal experiments(1)In the model group,damage to podocytes,focal segmental sclerosis,glomerular adhesion and intracapillary cell vacuolation were observed in some glomeruli,while in the intervention group,the damage to podocytes was less than that in the model group,and the number of glomeruli with focal segmental sclerosis was less than that in the model group.(2)The total 24-hour urinary protein and urinary protein/urinary creatinine values(T/Cr)were significantly higher in the model mice compared with the control and intervention groups.(3)The levels of Th17 cells in the mice in the intervention group were reduced on day 14 and 21 compared with the model group,and the levels of Treg cells were increased on day 14,21 and 28 compared with the model group,but these differences were not statistically significant.(4)The kidney IL-6,IL-17,IL-18,TNF-α and PCX expressions were reduced in the intervention group compared with the model group,but the differences were not statistically significant.Conclusions1 ACTH therapy may have a therapeutic effect in patients with hormone and second-line immunosuppressant-resistant FSGS.2 ACTH reduces urinary protein and attenuates renal damage in FSGS model mice via non-steroidal pathways,but this effect may not occur through modulation of Th17/Treg cell immune imbalance,protection of podocytes and suppression of immune inflammatory responses.