The Protective Effect Of Brown Adipose-derived Neuregulin 4 On Renal Inflammation With Diabetic Nephropathy

BackgroundDiabetic nephropathy(DN)is a common complication of diabetes and it is the leading cause of end-stage renal disease.The synergistic action of various inflammatory factors also promotes the occurrence and development of DN.Adipose tissue can be divided into brown adipose tissue(BAT)and white adipose tissue(WAT).The adipokines secreted from BAT have a pro-inflammatory response and can cause insulin resistance and atherosclerosis.However,the expression of major adipokines secreted by WAT is very low in BAT,so the endocrine and inflammatory effects of BAT remain unclear.Neuregulin 4(NRG4)is a protein with an epidermal growth factor-like structural domain that is expressed and secreted primarily by BAT,which can specifically bind to the receptor tyrosine protein kinase 4 receptor on the cell membrane surface and prevents cell apoptosis by antagonizing the release of inflammatory factors caused by tumor necrosis factor(TNF)and interferon(IFN)-γ.So far,some studies have shown that NRG4 has anti-inflammatory effect in adipose tissue and colon.In addition,it has been shown that brown adipose-derived NRG4 can reduce endothelial inflammatory damage and alleviate atherosclerosis.However,the effect of brown adipose-derived NRG4 on renal inflammation with DN remains unclear.ObjectiveTo investigate whether brown adipose-derived NRG4 can alleviate DN through inhibiting renal inflammatory response.MethodsC57BL/6J and NRG4 knockout mice were fed high-fat diet combined with intrabitoneal injection of streptozocin to construct the diabetes model.After the model establishment,the mice were grouped and injected with adeno-associated virus in the brown adipose tissue of the interscapular region.Then the mice were continued to be fed high-fat diet until the development of DN.After the experiment,the blood glucose and lipid-related indicators and serum levels of the inflammatory factors interleukin(IL)-1β,IL-6 and tumor necrosis factor-α(TNF-α)were measured.We collected the urine of mice to calculate the urinary albumin/creatinine ratio(UACR).The mouse body weight and kidney weight were recorded to calculate ratios.PAS staining and transmission electron microscopy were used to observe the podocyte injury and pathological glomerular changes.The expression of F4/80 in renal tissues was measured by immunohistochemistry.The mRNA expression of IL-1β,IL-6 and TNF-α in renal tissues were analyzed by real-time quantitative polymerase chain reaction.Results(1)The deficiency of NRG4 increased proteinuria and UACR levels in DN mice.After NRG4 supplementation,the urinary protein levels were significantly reduced.(2)In NRG4-deficient mice with DN,the glomerular volume increased,mesangial matrix hyperplasia and podococyte injury increased.After NRG4 supplementation,the glomerular pathological damage improved.(3)The deficiency of NRG4 significantly increased serum IL-1β、IL-6 and TNF-α levels and mRNA expression of L-1β、IL-6 and TNF-α in renal tissues.In addition,the F4/80 expression in kidney tissues was also increased.After NRG4 supplementation,serum inflammatory factor levels and the expression of mRNA were reduced,and macrophage infiltration decreased.(4)The deficiency of NRG4 aggravated the disorders of glucolipid metabolism and increased body weight.After NRG4 supplementation,disorders of glucolipid metabolism were improved and body weight was decreased.ConclusionBrown adipose-derived NRG4 can reduce renal inflammatory response,decrease proteinuria and alleviate renal injury in DN mice.