Epigenetic Regulation of Kidney Fibrosis following AKI

总结 急性肾损伤（AKI）的发作与慢性肾功能衰竭的风险增加有关。 慢性肾脏病（CKD）;肾功能的永久性丧失。AKI后，上皮细胞之间的串扰 和间质细胞是至关重要的肾脏愈合（适应性反应），但如果长期促进慢性肾病 （适应不良）。有证据表明，表观遗传修饰剂，如组蛋白脱乙酰酶， HDAC（HDAC）和microRNA（miR）可以变得紊乱，导致病理状况。为 例如，假设AKI后肾脏HDAC的激活会加重损伤;然而， 我们和其他人已经证明HDAC也是上皮修复所必需的。中的间隙 我们的知识存在于肾细胞类型特异性，HDAC亚型依赖性机制中， 修复或慢性损伤，以应对AKI。我们发现，在AKI后，HDAC1显著降低， 在肾皮质包括成纤维细胞和周细胞中增加。利用可诱导的成纤维细胞- 特异性HDAC1敲除（KO）小鼠，我们发现成纤维细胞/周细胞HDAC1导致 肌成纤维细胞活化和纤维化。HDAC 1的一个潜在靶点可能是miR-215 - 5p （miR215）。miR215通过体内HDAC抑制而减少，并且通过肾脏中的HDAC 1而增加 成纤维细胞/周细胞。我们提供了成纤维细胞miR215是促纤维化的数据。从这些数据来看， 目的1：为了验证AKI介导的细胞凋亡的假设， 纤维化依赖于成纤维细胞/周细胞HDAC 1的活化。目标2：测试 AKI促进肾脏中miR215依赖性间质纤维化的假设。的 本R01中提出的实验将为表观遗传调控提供深入的分子证据 AKI后肾脏成纤维细胞/周细胞的动态表观遗传学变化， CKD过渡期的模式化。使用有偏和无偏的方法将导致 鉴定可能具有治疗价值的新途径以帮助减轻AKI-CKD 过渡

SUMMARY Episodes of acute kidney injury (AKI) are associated with an increased risk for chronic kidney disease (CKD); a permanent loss of kidney function. Following AKI, crosstalk between epithelial and interstitial cells is critical for kidney healing (adaptive response) but if prolonged fosters CKD (maladaptive). Evidence suggests that epigenetic modifiers, such as histone deacetylases (HDACs) and microRNAs (miRs), can become deranged leading to pathological conditions. For example, activation of kidney HDACs following AKI is hypothesized to exacerbate injury; however, we and others have demonstrated that HDACs are also necessary for epithelial repair. A gap in our knowledge exists in the kidney cell type specific, HDAC isoform-dependent mechanisms of repair or chronic injury in response to AKI. We identified that following AKI, HDAC1 is significantly increased in the kidney cortex including in fibroblasts and pericytes. Utilizing inducible, fibroblast- specific HDAC1 knockout (KO) mice, we found that fibroblast/pericyte HDAC1 results in myofibroblast activation and fibrosis. One potential target of HDAC1 may be miR-215-5p (miR215). miR215 is reduced by in vivo HDAC inhibition, and is increased by HDAC1 in kidney fibroblast/pericyte cells. We provide data that fibroblast miR215 is profibrotic. From these data, we propose to test the following hypotheses: Aim 1: To test the hypothesis that AKI-mediated fibrosis is dependent on activation of fibroblast/pericyte cell HDAC1. Aim 2: To test the hypothesis that AKI promotes miR215 dependent interstitial fibrosis in the kidney. The experiments proposed in this R01 will provide deep molecular evidence of epigenetic regulation of the kidney fibroblast/pericytes following AKI and we will determine the dynamic epigenetic patterning during CKD transition. Using both biased and unbiased approaches will result in the identification of novel pathways that likely be of therapeutic value to help attenuate AKI-CKD transition.