Hemodynamic mechanisms of impaired recovery and progression of renal disease following AKI in preexisting CKD states

既往 CKD 状态下 AKI 后肾病恢复受损和进展的血流动力学机制

• 批准号: 10046795
• 负责人: Aaron James Polichnowski
• 金额: $ 44.4万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046795
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Animal Model; Antihypertensive Agents; Basic Science; Biochemical; Blood Pressure; Blood capillaries; Chronic; Chronic Disease; Chronic Kidney Failure; Clinical; Clinical Research; Clinical Sciences; Conscious; Data; Defect; Development; Disease Progression; Dysbarism; End stage renal failure; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Fibrosis; Functional disorder; Gap Junctions; Goals; Gold; High Prevalence; Homeostasis; Hypertension; Hypoxia; Immunologics; Impairment; Inflammation; Inflammatory; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Knowledge; Lead; Measurement; Mediating; Methodology; Modeling; Pathogenicity; Pathway interactions; Patients; Pericytes; Physiological; Population; Populations at Risk; Production; Quality of life; Rattus; Recovery; Renal Blood Flow; Renin-Angiotensin System; Reporting; Research; Risk; Role; Testing; Tubular formation; analytical method; blood pressure reduction; cytokine; density; experimental study; glomerulosclerosis; hemodynamics; improved; inhibitor/antagonist; injured; innovation; insight; instrument; mortality; novel; novel therapeutics; outcome forecast; prevent; therapeutic target; transmission process; treatment strategy

There is strong evidence that acute kidney injury (AKI) significantly increases the risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD). If AKI occurs in patients with CKD, the prognosis is significantly worse. Both clinical and basic science studies report that preexisting CKD impairs recovery from AKI and AKI accelerates the progression of preexisting CKD. However, the mechanisms contributing to such AKI-CKD interactions remain poorly understood. In this regard, two recent clinical studies indicate that administration of renin-angiotensin system (RAS) inhibitors during recovery from AKI significantly reduces mortality and CKD progression. Thus, administration of anti-hypertensive therapy (AHT) during a critical window following AKI may improve recovery and reduce the risk of CKD progression. As such, this proposal tests the hypothesis that the development or worsening of hypertension following AKI in preexisting CKD states impairs tubule recovery and is the major cause of the subsequent progression to ESRD. A novel rat model of the AKI–CKD nexus that we have shown recapitulates the impaired recovery from AKI and subsequent rapid progression to ESRD in the clinical setting will be used in the proposed studies. The first aim will investigate the role of hypertension and increased renal blood pressure transmission to promote renal inflammation, pericyte dysfunction, microvascular rarefaction, and hypoxia during recovery from AKI in preexisting CKD states. We propose that hypoxia hinders the ability of injured tubular epithelial cells to redifferentiate and regain function. To test this, we will administer RAS dependent and independent AHT’s beginning 1 week following AKI to assess the extent to which they alter renal pericyte density, capillary density, hypoxia, and tubular differentiation status. Consistent with our preliminary data, we anticipate that reducing BP, per se, will mitigate microvascular rarefaction and hypoxia, promote tubular epithelial cell redifferentiation, and reduce the development of fibrosis during recovery from AKI. We will also use multiplex ELISA cytokine arrays to determine the ability of different AHT’s to mitigate renal pro-inflammatory cytokine production during recovery from AKI in rats with preexisting CKD. Studies in Aim 2 will utilize gold standard blood pressure measurements in conscious, chronically instrumented rats to investigate the extent to which even modest increases in blood pressure following AKI in rats with preexisting CKD contribute to the progression of CKD. Novel analytical methodologies will also be used to assess renal blood flow autoregulation in conscious rats over several weeks after AKI. These studies employ an innovative animal model and physiological, biochemical, and immunological approaches to examine the poorly understood mechanisms contributing to impaired recovery and the rapid progression to ESRD after AKI in settings of preexisting CKD. In addition to providing novel insights into the clinical AKI-CKD nexus, these experiments may lead to new treatment strategies or therapeutic targets that could be used to improve recovery from AKI and reduce the subsequent risk of CKD progression in this at-risk population.

有强有力的证据表明急性肾损伤（AKI）会显着增加慢性肾病的风险 (CKD) 和终末期肾病 (ESRD) 如果 CKD 患者发生 AKI，则预后显着。 临床和基础科学研究均表明，已有的 CKD 会损害 AKI 和 AKI 的恢复。 加速已有 CKD 的进展 然而，导致 AKI-CKD 的机制。 在这方面，人们对相互作用的了解仍知之甚少，最近的两项临床研究表明，服用 AKI 恢复期间使用肾素-血管紧张素系统 (RAS) 抑制剂可显着降低死亡率和 CKD 因此，在 AKI 后的关键窗口期进行抗高血压治疗 (AHT)。 可能会改善康复并降低 CKD 进展的风险，因此，该提案检验了以下假设： 在先前存在的 CKD 状态下，AKI 后高血压的发展或恶化会损害肾小管的恢复 是随后进展为 ESRD 的主要原因。 我们已经展示了 AKI 恢复受损以及随后快速进展为 ESRD 的情况 临床环境将用于拟议的研究中，第一个目标是调查高血压的作用。 并增加肾血压传导，促进肾脏炎症、周细胞功能障碍， 先前存在的 CKD 状态下 AKI 恢复期间的微血管稀疏和缺氧。 缺氧会阻碍受损的肾小管上皮细胞重新分化和恢复功能的能力。 我们将在 AKI 后 1 周开始实施 RAS 依赖性和独立 AHT，以评估 它们改变肾周细胞密度、毛细血管密度、缺氧和肾小管分化状态的程度。 与我们的初步数据一致，我们预计降低血压本身将减轻微血管 稀疏缺氧，促进肾小管上皮细胞再分化，减少纤维化的发展 在 AKI 恢复期间，我们还将使用多重 ELISA 细胞因子阵列来确定不同的能力。 AHT 可减轻先前存在 AKI 的大鼠在 AKI 恢复过程中肾脏促炎细胞因子的产生 目标 2 中的 CKD 研究将利用金标准长期测量有意识的血压。 对大鼠进行仪器检测，以研究 AKI 后血压轻微升高的程度 已有 CKD 的大鼠也将有助于 CKD 的进展。 这些研究用于评估 AKI 后几周内清醒的肾大鼠的血流自动调节。 采用创新的动物模型和生理、生化和免疫学方法来检查 导致恢复受损和快速进展为 ESRD 的机制知之甚少 既存 CKD 背景下的 AKI 除了提供有关临床 AKI-CKD 关系的新见解之外，这些研究还提供了新的见解。 实验可能会产生新的治疗策略或治疗目标，可用于改善 从 AKI 中恢复并降低该高危人群随后发生 CKD 进展的风险。

项目成果

Autonomic and cholinergic mechanisms mediating cardiovascular and temperature effects of donepezil in conscious mice.

自主神经和胆碱能机制介导多奈哌齐对清醒小鼠的心血管和温度影响。

• DOI: 10.1152/ajpregu.00360.2019
• 发表时间: 2021
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Polichnowski,AaronJ;Williamson,GeoffreyA;Blair,TeshaE;Hoover,DonaldB
• 通讯作者: Hoover,DonaldB

Salt-Sensitive Hypertension, Renal Injury, and Renal Vasodysfunction Associated With Dahl Salt-Sensitive Rats Are Abolished in Consomic SS.BN1 Rats.

• DOI: 10.1161/jaha.120.020261
• 发表时间: 2021-11-02
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Potter JC;Whiles SA;Miles CB;Whiles JB;Mitchell MA;Biederman BE;Dawoud FM;Breuel KF;Williamson GA;Picken MM;Polichnowski AJ
• 通讯作者: Polichnowski AJ

Renal mass reduction increases the response to exogenous insulin independent of acid-base status or plasma insulin levels in rats.

肾质量减少增加了大鼠对外源胰岛素的反应，与酸碱状态或血浆胰岛素水平无关。

• DOI: 10.1152/ajprenal.00679.2020
• 发表时间: 2021
• 期刊: American journal of physiology. Renal physiology
• 作者: Mannon,ElinorC;Sartain,ChristinaL;Wilkes,TrevinC;Sun,Jingping;Polichnowski,AaronJ;O'Connor,PaulM
• 通讯作者: O'Connor,PaulM

A High Salt Diet Does Not Alter the Kinetics or the Magnitude of Renal Blood Flow Autoregulation in Conscious Salt-Resistant and Salt-Sensitive Rats.

高盐饮食不会改变有意识的耐盐和盐敏感大鼠的肾血流自动调节的动力学或幅度。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Polichnowski,AaronJ;Griffin,KarenA;Williamson,GeoffreyA;Bidani,AnilK
• 通讯作者: Bidani,AnilK