Research Paper Volume 13, Issue 6 pp 8524—8540

Combination CTLA-4 immunoglobulin treatment and ultrasound microbubble-mediated exposure improve renal function in a rat model of diabetic nephropathy

Liang Wang1, *, , Pengfei Wang1, *, , Xiuyun Li1, , Yanyan Dong1, , Senmin Wu1, , Maosheng Xu1, , Xiu Chen1, , Shijia Wang1, , Chao Zheng2, , Chunpeng Zou1, ,

  • 1 Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
  • 2 Department of Endocrinology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, China
* Equal contribution

Received: June 16, 2020       Accepted: February 1, 2021       Published: March 10, 2021
How to Cite

Copyright: © 2021 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Objective: This study explored the therapeutic impact of combined cytotoxic T lymphocyte-associated antigen 4 immunoglobulin (CTLA-4-Ig) treatment and microbubble-mediated exposure in a rat model of diabetic nephropathy (DN).

Method: We treated rats using CTLA-4-Ig and/or microbubble exposure. At 8 weeks post-intervention, key parameters were evaluated including blood biochemistry, damage to renal tissue, renal parenchymal elasticity, ultrastructural changes in podocytes, and renal parenchymal expression of CD31, CD34, IL-6, Fn, Collagen I, Talin, Paxillin, α3β1, podocin, nephrin, and B7-1.

Result: We found that renal function in the rat model of DN can be significantly improved by CTLA-4-Ig and CTLA-4-Ig + ultrasound microbubble treatment. Treatment efficacy was associated with reductions in renal parenchymal hardness, decreases in podocyte reduction, decreased IL-6, Fn and Collagen I expression, increased Talin, Paxillin and α3β1 expression, elevated podocin and nephrin expression, and decreased B7-1 expression. In contrast, these treatments did not impact CD31 or CD34 expression within the renal parenchyma.

Conclusion: These findings clearly emphasize that CTLA-4-Ig can effectively prevent podocyte damage, inhibiting inflammation and fibrosis, and thereby treating and preventing DN. In addition, ultrasound microbubble exposure can improve the ability of CTLA-4-Ig to pass through the glomerular basement membrane in order to access podocytes such that combination CTLA-4-Ig + microbubble exposure treatment is superior to treatment with CTLA-4-Ig only.


DN: diabetic nephropathy; CTLA-4-Ig: Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin; FBG: fasting blood glucose; ALT: alanine aminotransferase; AST: aspartate aminotransferase; Ccr: creatinine clearance; UAER: urinary albumin excretion rate; KW/BW: kidney weight/body weight; TEM: transmission electron microscope; SD: Sprague Dawley; STZ: Streptozotocin; UVPM: urine volume per minute; Ucr: urine creatinine; BW: body weight; Scr: serum creatinine; PFA: paraformaldehyde; PBS: phosphate-buffered saline.