Inhibition Of Renal Injury

急性肾损伤(以前称为急性肾功能衰竭)具有很高的发病率和死亡率。在建立了一种新的脓毒症诱导的AKI模型后，我们正在使用该模型来研究损伤的病理生理学，筛选药物，并研究其作用机制，包括通过遥测有意识的血压。我们调整了我们的小鼠模型，使用了在较小年龄发展为AKI的杂交小鼠，我们建立了另一个使用共病的模型，即先前存在的肾功能障碍，这被认为增加了患者对AKI的易感性。这种急性-慢性综合征还没有在动物身上进行研究，肾脏病领域正试图获得更多关于这一现象在患者中如何表现的信息。 由于我们用于先前存在的肾功能障碍的模型是可逆的，与在CKD患者中看到的进展不同，我们从部分肾切除(5/6肾切除)程序开始，这是一个经典的大鼠CKD模型，然后将其适应于小鼠。我们已经确定了我们的模型的特征，它具有进展性CKD的几个特征，包括高血压、蛋白尿、肾小球硬化、间质肾小管纤维化、贫血和心脏纤维化。为了使我们的CKD小鼠模型与我们的脓毒症AKI模型兼容，我们测试了三个对CKD具有不同敏感性的小鼠品系。在最敏感的菌株中，血管紧张素受体阻滞剂(奥美沙坦)可以降低CKD的所有方面。相反，血管紧张素II可以将耐药菌株转化为敏感菌株。然而，这种影响在很大程度上不依赖于血压。 1)我们结合了我们的新的进展性CKD小鼠模型和我们的小鼠脓毒症-AKI模型来研究‘急性-慢性’综合征。我们发现，CKD增加了包括AKI在内的所有脓毒症严重程度的指标。脓毒症的一个共同特征是脾细胞的凋亡。令人惊讶的是，我们发现在没有脓毒症的情况下，CKD增加了脾细胞的凋亡，这与CKD的严重程度相一致。这是CKD诱导脾细胞凋亡的首次证明。CKD增强脓毒症诱导的细胞因子的增加，包括血管内皮生长因子和HMGB1。可溶性Flt1是一种血管内皮生长因子结合肽，可降低脓毒症的严重程度，但对急慢性小鼠无效。相反，在抗HMGB1中和抗体治疗败血症小鼠无效的剂量下，抗HMGB1抗体改善了急慢性感染小鼠的脓毒症严重程度。脾切除术暂时降低了循环中的HMGB1水平，在低谷期间，抗HMGB1中和抗体不再有效地治疗急慢性小鼠，这支持了脾作为HMGB1的一个潜在来源。尽管CKD加重了基线高血压，但感染脓毒症的CD-1小鼠比感染的对照小鼠更快地变得低血压。 我们继续探索脓毒症-AKI、CKD和急性-慢性肾脏疾病的潜在机制和治疗方法。

Acute kidney injury (previously known as acute renal failure) has a high morbidity and mortality. After developing a novel model of sepsis-induced AKI that employs cecal ligation puncture in elderly mice treated with fluids and antibiotics, we are using the model to study the pathophysiology of injury, to screen drugs, and to study their mechanisms of action, including conscious blood pressure by telemetry. We adjusted our mouse model by using outbred mice, which develop AKI at a younger age, and we established another model using comorbidity, namely pre-existing renal dysfunction, which is thought to increase susceptibility to AKI in patients. This acute-on-chronic syndrome has not been studied in animals, and the nephrology field is trying to gain more information about how this is manifest in patients. Because the model we used for pre-existing renal dysfunction is reversible, unlike the progression seen in CKD patients, we started with a partial renal ablation (5/6 nephrectomy) procedure, a classic rat CKD model, then adapted it to the mouse. We have characterized our model, and it has several hallmarks of progressive CKD, including hypertension, proteinuria, glomerulosclerosis, interstitial renal tubular fibrosis, anemia, and cardiac fibrosis. In order to make our CKD mouse model compatible with our sepsis AKI models, we tested three mouse strains, which had differential susceptibility to CKD. In the most susceptible strain, all aspects of CKD could be lowered by an angiotensin receptor blocker (olmesartan). Conversely, angiotensin II could convert a resistant strain to a susceptible strain. However, this effect is largely independent of blood pressure. 1) We combined our new mouse model for progressive CKD and our mouse sepsis-AKI model to study the 'acute-on-chronic' syndrome. We found that all indices of sepsis severity, including AKI, were increased by CKD. One common feature of sepsis is apoptosis of spleen cells. Surprisingly, we found that in the absence of sepsis, CKD increased spleen apoptosis, and this corresponded with the severity of CKD. This is the first demonstration of CKD-induced spleen apoptosis. CKD enhanced sepsis-induced increases in cytokines, including VEGF and HMGB1. Soluble-FLT1, a VEGF-binding peptide, decreased the severity of sepsis, but was ineffective in treating acute-on-chronic mice. Conversely, at a dose that anti-HMGB1 neutralizing antibody was ineffective in treating septic mice, anti-HMGB1 improved sepsis severity in acute-on-chronic mice. Splenectomy transiently decreased circulating HMGB1 levels, and during the trough anti-HMGB1 neutralizing antibodies were no longer effective in treating acute-on-chronic mice, which supports the spleen as one potential source of HMGB1. Despite baseline hypertension that was exacerbated by CKD, the CD-1 mice subjected to sepsis became hypotensive more rapidly than control mice subjected to sepsis. We continue to explore potential mechanisms and treatments for sepsis-AKI, CKD, and acute-on-chronic kidney disease.