Kidney Institute of PLA, Department of Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, People's Republic of China; Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of T.C.M, People's Republic of China.
Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA.
Kidney Int. 2017 Nov;92(5):1178-1193. doi: 10.1016/j.kint.2017.03.037. Epub 2017 Jun 24.
Large epidemiological studies clearly demonstrate that multiple episodes of acute kidney injury contribute to the development and progression of kidney fibrosis. Although our understanding of kidney fibrosis has improved in the past two decades, we have limited therapeutic strategies to halt its progression. Myofibroblast differentiation and proliferation remain critical to the progression of kidney fibrosis. Although canonical Wnt signaling can trigger the activation of myofibroblasts in the kidney, mediators of Wnt inhibition in the resident progenitor cells are unclear. Recent studies demonstrate that the loss of a Krüppel-like factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, exacerbates kidney fibrosis in murine models. Here, we tested whether Klf15 mRNA and protein expression are reduced in late stages of fibrosis in mice that underwent unilateral ureteric obstruction, a model of progressive renal fibrosis. Knockdown of Klf15 in Foxd1-expressing cells (Foxd1-Cre Klf15fl/fl) increased extracellular matrix deposition and myofibroblast proliferation as compared to wildtype (Foxd1-Cre Klf15+/+) mice after three and seven days of ureteral obstruction. This was validated in mice receiving angiotensin II treatment for six weeks. In both these murine models, the increase in renal fibrosis was found in Foxd1-Cre Klf15 mice and accompanied by the activation of Wnt/β-catenin signaling. Furthermore, knockdown of Klf15 in cultured mouse embryonic fibroblasts activated canonical Wnt/β-catenin signaling, increased profibrotic transcripts, and increased proliferation after treatment with a Wnt1 ligand. Conversely, the overexpression of KLF15 inhibited phospho-β-catenin (Ser552) expression in Wnt1-treated cells. Thus, KLF15 has a critical role in attenuating kidney fibrosis by inhibiting the canonical Wnt/β-catenin pathway.
大量的流行病学研究清楚地表明，多次急性肾损伤会导致肾脏纤维化的发生和进展。尽管在过去的二十年中，我们对肾脏纤维化的认识有所提高，但我们治疗的策略有限，无法阻止其进展。肌成纤维细胞的分化和增殖仍然是肾脏纤维化进展的关键。虽然经典的 Wnt 信号可以触发肾脏中肌成纤维细胞的激活，但驻留祖细胞中 Wnt 抑制的介质尚不清楚。最近的研究表明，缺失一种肾脏丰富的锌指转录因子 Krüppel 样因子 15（KLF15）会加剧小鼠模型中的肾脏纤维化。在这里，我们检测了在单侧输尿管梗阻（一种进行性肾纤维化模型）后，纤维化晚期的小鼠中 Klf15 mRNA 和蛋白表达是否减少。与野生型（Foxd1-Cre Klf15+/+）小鼠相比，在输尿管梗阻后 3 天和 7 天，Foxd1 表达细胞（Foxd1-Cre Klf15fl/fl）中的 Klf15 敲低增加了细胞外基质沉积和肌成纤维细胞增殖。在接受血管紧张素 II 治疗 6 周的小鼠中也验证了这一点。在这两种小鼠模型中，在 Foxd1-Cre Klf15 小鼠中发现了肾脏纤维化的增加，并且伴随着 Wnt/β-catenin 信号的激活。此外，在培养的小鼠胚胎成纤维细胞中敲低 Klf15 可激活经典的 Wnt/β-catenin 信号通路，增加致纤维化转录物，并在 Wnt1 配体处理后增加增殖。相反，KLF15 的过表达抑制了 Wnt1 处理细胞中磷酸化 β-catenin（Ser552）的表达。因此，KLF15 通过抑制经典的 Wnt/β-catenin 通路在减轻肾脏纤维化中起着关键作用。
