Department of Nephrology, Inje University, Busan, South Korea.
BMC Nephrol. 2011 Jun 16;12:27. doi: 10.1186/1471-2369-12-27.
Renal kallikrein (KLK1) synthesis and urinary excretion are reportedly diminished during AKI (acute kidney injury) in animal models, and provision of kallikrein abrogates renal injury in this setting, but data in human AKI is limited. Therefore we first examined KLK1 renal excretion in human AKI, and then probed potential endocrine and epigenetic mechanisms for its alterations.
KLK1 enzymatic activity excretion was evaluated in urine from patients with established or incipient AKI, versus healthy/non-hospital as well as ICU controls. Endocrine control of KLK1 excretion was then probed by catecholamine and aldosterone measurements in established AKI versus healthy controls. To examine epigenetic control of KLK1 synthesis, we tested blood and urine DNA for changes in promoter CpG methylation of the KLK1 gene, as well as LINE-1 elements, by bisulfite sequencing.
Patients with early/incipient AKI displayed a modest reduction of KLK1 excretion, but unexpectedly, established AKI displayed substantially elevated urine KLK1 excretion, ~11-fold higher than healthy controls, and ~3-fold greater than ICU controls. We then probed potential mechanisms of the change. Established AKI patients had lower SBP, higher heart rate, and higher epinephrine excretion than healthy controls, though aldosterone excretion was not different. Promoter KLK1 CpG methylation was higher in blood than urine DNA, while KLK1 methylation in blood DNA was significantly higher in established AKI than healthy controls, though KLK1 methylation in urine tended to be higher in AKI, directionally consistent with earlier/incipient but not later/established changes in KLK1 excretion in AKI. On multivariate ANOVA, AKI displayed coordinate changes in KLK1 excretion and promoter methylation, though directionally opposite to expectation. Control (LINE-1 repetitive element) methylation in blood and urine DNA was similar between AKI and controls.
Unexpectedly, increased KLK1 excretion in AKI patients was found; this increase is likely to be due in part to increments in adrenergic tone during BP depression. Epigenetic changes at KLK1 may also play a role in early changes of KLK1 expression and thus AKI susceptibility or recovery.
据报道，在动物模型的急性肾损伤（AKI）中，肾激肽（KLK1）的合成和尿排泄减少，而在这种情况下提供激肽可消除肾损伤，但 AKI 患者的数据有限。因此，我们首先检查了人类 AKI 中的 KLK1 肾排泄，然后探讨了其改变的潜在内分泌和表观遗传机制。
评估了已确诊或初发 AKI 患者与健康/非住院患者以及 ICU 对照组的尿液 KLK1 酶活性排泄。通过儿茶酚胺和醛固酮测量，在已确诊 AKI 患者与健康对照组中，进一步探究 KLK1 排泄的内分泌控制。为了检查 KLK1 合成的表观遗传控制，我们通过亚硫酸氢盐测序检测了血液和尿液中 KLK1 基因启动子 CpG 甲基化以及 LINE-1 元件的变化。
早期/初发 AKI 患者的 KLK1 排泄略有减少，但出乎意料的是，已确诊 AKI 患者的尿液 KLK1 排泄显著升高，比健康对照组高约 11 倍，比 ICU 对照组高约 3 倍。然后，我们探究了变化的潜在机制。与健康对照组相比，已确诊 AKI 患者的 SBP 较低，心率较高，肾上腺素排泄较高，而醛固酮排泄无差异。与尿液 DNA 相比，血液中 KLK1 启动子的 CpG 甲基化较高，而与健康对照组相比，已确诊 AKI 患者的血液 DNA 中 KLK1 甲基化明显较高，尽管 AKI 患者的 KLK1 甲基化倾向于升高，但与 AKI 中 KLK1 排泄的早期/初发变化方向一致，而与晚期/已确诊变化不一致。在多元方差分析中，AKI 患者的 KLK1 排泄和启动子甲基化呈协调变化，但与预期方向相反。AKI 患者和对照组的血液和尿液 DNA 中的对照（LINE-1 重复元件）甲基化相似。
出乎意料的是，发现 AKI 患者的 KLK1 排泄增加；这种增加可能部分归因于血压下降期间肾上腺素能张力的增加。KLK1 上的表观遗传变化也可能在 KLK1 表达的早期变化以及 AKI 易感性或恢复中发挥作用。
