Matsuda Hiroyuki, Hamet Pavel, Tremblay Johanne
Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada,
J Nephrol. 2014 Aug;27(4):351-60. doi: 10.1007/s40620-014-0054-3. Epub 2014 Feb 11.
Hypertension is a risk factor for renal impairment. While treatment of hypertension provides significant renal protection, there is still an unmet need requiring further exploration of additional pathogenetic mechanisms. We have found that the hypertension-related, calcium-regulated gene (HCaRG/COMMD5) is involved in renal repair. HCaRG is a small intracellular protein of 225 amino acids and its gene expression is negatively regulated by extracellular calcium concentrations. HCaRG is mostly expressed in the kidneys, with higher levels found in the spontaneously hypertensive rat than in normotensive rats. In an acute kidney injury model, HCaRG expression decreases immediately after injury but increases above baseline during the repair phase. In cell cultures, HCaRG has been shown to facilitate differentiation and to inhibit cell proliferation via p21 transactivation through the p53-independent signaling pathway. Induction of p21 independently of p53 is also observed in transgenic mice overexpressing HCaRG during the repair phase after ischemia/reperfusion injury, resulting in their improved renal function and survival with rapid re-differentiation of proximal tubular epithelial cells. In addition, transgenic mice recover rapidly from the inflammatory burst most likely as a result of maintenance of the tubular epithelial barrier. Recent studies indicate that facilitating re-differentiation and cell cycle regulation in injured renal proximal tubules might be important functions of HCaRG. We have proposed that HCaRG is a component of differential genetic susceptibility to renal impairment in response to hypertension.
高血压是肾功能损害的一个危险因素。虽然高血压治疗可提供显著的肾脏保护作用，但仍存在未满足的需求，需要进一步探索其他发病机制。我们发现，与高血压相关的钙调节基因（HCaRG/COMMD5）参与肾脏修复。HCaRG是一种由225个氨基酸组成的小细胞内蛋白，其基因表达受细胞外钙浓度的负调控。HCaRG主要在肾脏中表达，在自发性高血压大鼠中的表达水平高于正常血压大鼠。在急性肾损伤模型中，HCaRG表达在损伤后立即下降，但在修复阶段增加至基线以上。在细胞培养中，HCaRG已被证明可通过p53非依赖信号通路激活p21来促进分化并抑制细胞增殖。在缺血/再灌注损伤后的修复阶段，在过表达HCaRG的转基因小鼠中也观察到p21的非p53依赖性诱导，导致其肾功能改善和存活率提高，近端肾小管上皮细胞快速重新分化。此外，转基因小鼠很可能由于肾小管上皮屏障的维持而迅速从炎症爆发中恢复。最近的研究表明，促进损伤的肾近端小管中的重新分化和细胞周期调节可能是HCaRG的重要功能。我们提出，HCaRG是对高血压引起的肾功能损害的差异遗传易感性的一个组成部分。
