Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, China.
Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, 510515, Guangzhou, China.
Cell Death Differ. 2019 Dec;26(12):2774-2789. doi: 10.1038/s41418-019-0336-3. Epub 2019 Apr 25.
Kidney fibroblasts play a crucial role in dictating tubular cell fate and the outcome of acute kidney injury (AKI). The underlying mechanisms remain to be determined. Here, we found that mTOR signaling was activated in fibroblasts from mouse kidneys with ischemia/reperfusion injury (IRI). Ablation of fibroblast Rheb or Rictor promoted, while ablation of fibroblast Tsc1 protected against tubular cell death and IRI in mice. In tubular cells cultured with conditioned media (CM) from Rheb or Rictor fibroblasts, less hepatocyte growth factor (HGF) receptor c-met signaling activation or staurosporine-induced cell apoptosis was observed. While CM from Tsc1 fibroblasts promoted tubular cell c-met signaling activation and inhibited staurosporine-induced cell apoptosis. In kidney fibroblasts, blocking mTOR signaling downregulated the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and HGF. Downregulating fibroblast HGF expression or blocking tubular cell c-met signaling facilitated tubular cell apoptosis. Notably, renal PPARγ and HGF expression was less in mice with fibroblast Rheb or Rictor ablation, but more in mice with fibroblast Tsc1 ablation than their littermate controls, respectively. Together, these data suggest that mTOR signaling activation in kidney fibroblasts protects against tubular cell death and dictates the outcome of AKI through stimulating PPARγ and HGF expression.
肾成纤维细胞在决定肾小管细胞命运和急性肾损伤 (AKI) 的结局方面起着至关重要的作用。其潜在机制仍有待确定。在这里，我们发现缺血/再灌注损伤 (IRI) 小鼠肾脏中的成纤维细胞中 mTOR 信号被激活。成纤维细胞 Rheb 或 Rictor 的缺失促进了，而成纤维细胞 Tsc1 的缺失则保护了肾小管细胞免受死亡和 IRI 的影响。在培养的肾小管细胞中，用 Rheb 或 Rictor 成纤维细胞的条件培养基 (CM) 培养时，观察到更少的肝细胞生长因子 (HGF) 受体 c-met 信号激活或司他夫定诱导的细胞凋亡。而 Tsc1 成纤维细胞的 CM 则促进了肾小管细胞 c-met 信号的激活，并抑制了司他夫定诱导的细胞凋亡。在肾成纤维细胞中，阻断 mTOR 信号会下调过氧化物酶体增殖物激活受体 γ (PPARγ) 和 HGF 的表达。下调成纤维细胞 HGF 表达或阻断肾小管细胞 c-met 信号促进了肾小管细胞的凋亡。值得注意的是，与野生型对照相比，Rheb 或 Rictor 成纤维细胞缺失的小鼠肾脏中的成纤维细胞和肾小管细胞的 PPARγ 和 HGF 表达减少，但 Tsc1 成纤维细胞缺失的小鼠则增加。总之，这些数据表明，肾成纤维细胞中 mTOR 信号的激活通过刺激 PPARγ 和 HGF 的表达，保护肾小管细胞免受死亡，并决定 AKI 的结局。
