Background

Bone marrow stromal cells (BMSCs) are an effective new strategy for the treatment of kidney diseases. At present, noninvasive and efficient transplantation approaches to homing BMSCs to the renal parenchyma is still a serious challenge. The aim of this study was to investigate the feasibility and potential mechanism of ultrasound-guided intraparenchymal transplantation of BMSCs for the treatment of adriamycin nephropathy (AN) in rats.

Materials and methods

A rat AN model was induced by 2 injections of doxorubicin. The rats were randomly divided into 4 groups (n = 10 animals in each group) : normal group (N group, no treatment), control medium group (CM group, transplant medium 1.0 mL), adriamycin nephropathy group (ADR group, phosphate buffered saline 1.0 mL), or BMSCs group (BMSCs fluid 1.0 mL). Intraparenchymal injection was completed under ultrasound guidance. After 4 weeks of treatment, blood samples were collected for serum biochemical measurements and ELISAs. The kidneys were removed for histopathological examination, electron microscopy, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), and western blot analysis.

Results

No deaths occurred in any group after BMSCs transplantation through the renal parenchyma under ultrasound guidance. Compared with the N and CM groups, in the ADR group, blood serum creatinine (SCr), blood urea nitrogen (BUN) and urine albumin (ALb) were higher, glomerular and tubular dilatation was observed, the number of apoptotic cells was higher, and the protein levels of receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL) and nucleotide leukin-rich polypeptide 3 (NLRP3), key components of pathways in rat kidney, were significantly higher. Compared with those in the ADR group, the levels of SCr, BUN, ALb and serum proinflammatory cytokines in the BMSCs group were lower, the pathological structure of the kidney was improved, the number of apoptotic cells was lower, and the levels of RIPK3/MLKL and NLRP3 were significantly lower.

Conclusion

Ultrasound-guided intraparenchymal transplantation of BMSCs regulated the RIPK3/MLKL and NLRP3 pathways in a minimally invasive and safe manner, thereby inhibiting renal necrosis and inflammation and playing a protective role in rat AN.

中文翻译：

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超声引导下骨髓间充质干细胞移植通过RIPK3/MLKL和NLRP3通路对阿霉素肾病大鼠的保护作用

背景

骨髓基质细胞（BMSCs）是治疗肾脏疾病的有效新策略。目前，将骨髓间充质干细胞归巢到肾实质的无创高效移植方法仍然是一个严峻的挑战。本研究旨在探讨超声引导下骨髓间充质干细胞实质内移植治疗大鼠阿霉素肾病（AN）的可行性和潜在机制。

材料和方法

通过2次注射多柔比星诱导大鼠AN模型。将大鼠随机分为4组（每组n=10只）：正常组（N组，未处理）、对照培养基组（CM组，移植培养基1.0 mL）、阿霉素肾病组（ADR组，磷酸盐缓冲液）生理盐水 1.0 mL），或 BMSCs 组（BMSCs 液 1.0 mL）。在超声引导下完成脑实质内注射。治疗 4 周后，收集血样用于血清生化测量和 ELISA。取出肾脏进行组织病理学检查、电子显微镜检查、末端脱氧核苷酸转移酶 dUTP 缺口末端标记 (TUNEL) 和蛋白质印迹分析。

结果

超声引导下经肾实质移植BMSCs后各组均无死亡病例。与 N 组和 CM 组相比，ADR 组血清肌酐（SCr）、血尿素氮（BUN）和尿白蛋白（ALb）均较高，肾小球及肾小管扩张，凋亡细胞数较多，受体相互作用蛋白激酶 3 (RIPK3)/混合谱系激酶结构域样蛋白 (MLK​​L) 和富含核苷酸白介素多肽 3 (NLRP3) 是大鼠肾脏通路的关键成分，其蛋白水平显着升高。与ADR组相比，BMSCs组SCr、BUN、ALb及血清促炎细胞因子水平降低，肾脏病理结构改善，凋亡细胞数量减少，

结论

超声引导下骨髓间充质干细胞实质内移植以微创、安全的方式调节 RIPK3/MLKL 和 NLRP3 通路，从而抑制肾坏死和炎症，对大鼠 AN 起保护作用。