Abstract
Objective This study is aimed at investigating the efficacy of CTLA4-Ig abatacept in normalizing proteinuria and its possible mechanism in adriamycin-induced nephropathy (AIN) rats. Methods A total of 32 healthy male Sprague-Dawley rats were randomly divided into a normal group, an AIN group, an abatacept group, and a prednisone group. Adriamycin (6.5 mg/kg) was injected once via the tail vein of rats to induce nephrotic syndrome. After adriamycin treatment, the abatacept group rats were given abatacept (0.5 mg/kg) once by intraperitoneal injection on day 14. In addition, the prednisone group rats were given prednisone (12.5 mg/kg) daily consecutively by gavage from day 14 to day 21. Blood, urine, and kidney tissue specimens were collected when sacrificed on day 21. The 24-hour urinary protein, serum albumin, cholesterol, creatinine, and urea nitrogen were then detected. An enzyme-linked immunosorbent assay was used to determine the level of urine CD80 and serum IL-17. Flow cytometry was used to investigate the prevalence of circulating Treg. Hematoxylin-eosin staining and electron microscopy were used for a renal histological study. Immunofluorescence staining was performed to confirm the CD80 expression of renal tissue. Results The 24-hour urinary protein of the abatacept group was significantly lower than that of the prednisone group and the AIN group. The level of urine CD80 of the abatacept group was significantly lower than that of the AIN group. Compared with the AIN group and the prednisone group, the circulating Treg prevalence of the abatacept group was significantly higher, while the level of serum IL-17 was lower. A negative kidney staining of CD80 expression was demonstrated in each group in this study. The 24-hour urinary protein had a negative correlation with the circulating Treg prevalence and Treg/IL-17 and a positive correlation with the urine CD80 and serum IL-17. Urinary CD80 had a positive correlation with serum IL-17 and no correlation with the circulating Treg prevalence. Conclusions CTLA4-Ig abatacept can reduce proteinuria of adriamycin-induced nephropathy rats, possibly at least partially as a result of regulating circulating Treg/IL-17. CTLA4-Ig abatacept could be a promising regimen for idiopathic nephrotic syndrome.
Highlights
Idiopathic nephrotic syndrome (INS) is a highly prevalent glomerular disease that is characterized by massive proteinuria, hypoalbuminemia, hypercholesterolemia, and edema in childhood
After adaptive feeding for one week, rats without proteinuria were randomly divided into the normal group (n = 8), the adriamycin-induced nephropathy (AIN) group (n = 8), the abatacept group (n = 8), and the prednisone group (n = 8)
All of the rats manifested with proteinuria (3+) on day 14
Summary
Idiopathic nephrotic syndrome (INS) is a highly prevalent glomerular disease that is characterized by massive proteinuria, hypoalbuminemia, hypercholesterolemia, and edema in childhood. Minimal change disease (MCD) and focal and segmental glomerulosclerosis (FSGS), considered podocytopathy, are the most common renal histopathologies. Some patients are resistant to current treatment regimens and progress to end-stage renal disease (ESRD) [4]. The exploration of new treatment options is of great clinical importance. The clinical application of cytotoxic T-lymphocyte-associated agent 4-immunoglobulin fusion protein (CTLA4-Ig) abatacept in proteinuric kidney disease cases has highlighted a new therapeutic option for INS [5,6,7,8,9]. Yu and colleagues first reported five patients with primary or recurrent FSGS, who showed a positive response to abatacept [5]. The same effective results were subsequently determined in other MCD and FSGS patients
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