中性粒细胞趋化因子 MIP3 减少肥胖 Dahl 盐敏感型幼鼠肾脏免疫细胞浸润和进行性肾损伤。
Neutralizing MIP3 Reduces Renal Immune Cell Infiltration and Progressive Renal Injury in Young Obese Dahl Salt-Sensitive Rats.
机构信息
Departments of Pharmacology and Toxicology and Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi.
Departments of Pharmacology and Toxicology and Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi
出版信息
J Pharmacol Exp Ther. 2023 Mar;384(3):445-454. doi: 10.1124/jpet.122.001298. Epub 2022 Dec 5.
Recently, we reported that the early progression of renal injury in obese Dahl salt-sensitive leptin receptor mutant (SSmutant) rats was associated with increased macrophage inflammatory protein 3- (MIP3) expression prior to puberty. Therefore, this study tested the hypothesis that MIP3 plays a role in recruiting immune cells, thereby triggering renal inflammation and early progressive renal injury in SSmutant rats prior to puberty. Four-week-old Dahl salt-sensitive (SS) and SSmutant rats either served as control (IgG; intraperitoneal, every other day) or received MIP3-neutralizing antibody (MNA; 100 µg/kg) for 4 weeks. MNA reduced circulating and renal MIP3 levels and proinflammatory immune cells by 50%. Although MNA treatment did not affect blood glucose and plasma cholesterol levels, MNA markedly decreased insulin resistance and triglyceride levels in SSmutant rats. We observed no differences in mean arterial pressure (MAP) between SS and SSmutant rats, and MNA had no effect on MAP in either strain. Proteinuria was significantly increased in SSmutant rats versus SS rats over the course of the study. Treatment with MNA markedly decreased proteinuria in SSmutant rats while not affecting SS rats. Also, MNA decreased glomerular and tubular injury and renal fibrosis in SSmutant rats while not affecting SS rats. Overall, these data indicate that MIP3 plays an important role in renal inflammation during the early progression of renal injury in obese SSmutant rats prior to puberty. These data also suggest that MIP3 may be a novel therapeutic target to inhibit insulin resistance and prevent progressive proteinuria in obese children. SIGNIFICANCE STATEMENT: Childhood obesity is increasing at an alarming rate and is now being associated with renal disease. Although most studies have focused on the mechanisms of renal injury associated with adult obesity, few studies have examined the mechanisms of renal injury involved during childhood obesity. In the current study, we observed that the progression of renal injury in obese Dahl salt-sensitive leptin receptor mutant rats was associated with an increase in MIP3, a chemokine, before puberty, and inhibition of MIP3 markedly reduced renal injury.
最近，我们报道肥胖型道利盐敏感型瘦素受体突变（SSmutant）大鼠的早期肾损伤进展与青春期前巨噬细胞炎症蛋白 3-（MIP3）表达增加有关。因此，本研究测试了这样一个假设，即 MIP3 在招募免疫细胞方面发挥作用，从而触发青春期前肥胖型 SSmutant 大鼠的肾脏炎症和早期进行性肾损伤。将 4 周龄的道利盐敏感型（SS）和 SSmutant 大鼠作为对照（IgG；腹腔内，每隔一天一次），或接受 MIP3 中和抗体（MNA；100μg/kg）治疗 4 周。MNA 使循环和肾脏中的 MIP3 水平和促炎免疫细胞降低 50%。尽管 MNA 治疗并未影响血糖和血浆胆固醇水平，但 MNA 显著降低了 SSmutant 大鼠的胰岛素抵抗和甘油三酯水平。我们观察到 SS 和 SSmutant 大鼠之间的平均动脉压（MAP）没有差异，并且 MNA 对两种品系的 MAP 均无影响。在研究过程中，SSmutant 大鼠的蛋白尿显著高于 SS 大鼠。MNA 治疗显著降低了 SSmutant 大鼠的蛋白尿，而对 SS 大鼠没有影响。此外，MNA 降低了 SSmutant 大鼠的肾小球和肾小管损伤以及肾脏纤维化，而对 SS 大鼠没有影响。总体而言，这些数据表明 MIP3 在青春期前肥胖型 SSmutant 大鼠的早期肾损伤进展过程中在肾脏炎症中发挥重要作用。这些数据还表明，MIP3 可能是抑制胰岛素抵抗和预防肥胖儿童进行性蛋白尿的新的治疗靶点。
意义陈述
儿童肥胖症的发病率正在以惊人的速度增长，现在与肾脏疾病有关。尽管大多数研究都集中在与成人肥胖相关的肾脏损伤机制上，但很少有研究研究与儿童肥胖相关的肾脏损伤机制。在本研究中，我们观察到肥胖型道利盐敏感型瘦素受体突变大鼠的肾损伤进展与青春期前趋化因子 MIP3 的增加有关，而 MIP3 的抑制可显著降低肾损伤。
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