Epigenetic Regulation of Kidney Fibrosis following AKI

摘要 急性肾损伤(AKI)的发作与慢性肾脏的风险增加有关 疾病(CKD)；肾功能的永久性丧失。继AKI后，上皮细胞之间的串扰 间质细胞对肾脏愈合(适应性反应)至关重要，但如果延长时间会导致慢性肾脏病 (适应不良)。有证据表明，表观遗传修饰物，如组蛋白脱乙酰酶 (HDACs)和microRNAs(MiRs)，可能会变得错乱，导致病理情况。为 例如，AKI后肾脏HDAC的激活被认为会加剧损伤；然而， 我们和其他人已经证明，HDAC也是上皮修复所必需的。在…方面的差距 我们的知识存在于肾脏细胞类型特异的、HDAC异构体依赖的机制中 修复或慢性损伤，以回应AKI。我们发现，在AKI之后，HDAC1显著 在肾皮质增加，包括成纤维细胞和周细胞。利用可诱导的成纤维细胞- 特定的HDAC1基因敲除(KO)小鼠，我们发现成纤维细胞/周细胞HDAC1导致 肌成纤维细胞活化与纤维化。HDAC1的一个潜在靶点可能是miR-215-5p (MiR215)。在体内，miR215被HDAC抑制而减少，而在肾脏中被HDAC1增加 成纤维细胞/周细胞。我们提供的数据表明，成纤维细胞miR215具有促纤维化作用。从这些数据来看， 我们建议检验以下假设：目标1：检验AKI介导的 纤维化依赖于成纤维细胞/周细胞细胞HDAC1的激活。目标2：测试 假设AKI促进miR215依赖性肾间质纤维化。这个 R01中提出的实验将提供表观遗传调控的深层分子证据 我们将确定AKI后肾脏成纤维细胞/周细胞的动态表观遗传学 CKD转变过程中的图案化。同时使用有偏见和无偏见的方法将导致 识别可能有助于减轻AKI-CKD的治疗价值的新途径 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.