Department of Nephrology, Monash Medical Centre, Monash University, Melbourne, Victoria, Australia.
Centre for Inflammatory Diseases, Monash University, Melbourne, Victoria, Australia.
Nephrology (Carlton). 2019 Sep;24(9):983-991. doi: 10.1111/nep.13635. Epub 2019 Jul 31.
Protease-activated receptor 2 (PAR2) has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR2 in cultured tubular epithelial cells induces extracellular signal-regulated kinase signalling and secretion of fibronectin, C-C Motif Chemokine Ligand 2 (CCL2) and transforming growth factor-β1 (TGF-β1), suggesting a role in tubulointerstitial inflammation and fibrosis. We tested this hypothesis in unilateral ureteric obstruction (UUO) in which ongoing tubular epithelial cell damage drives tubulointerstitial inflammation and fibrosis.
Unilateral ureteric obstruction surgery was performed in groups (n = 9/10) of Par2-/- and wild type (WT) littermate mice which were killed 7 days later. Non-experimental mice were controls.
Wild type mice exhibited a 5-fold increase in Par2 messenger RNA (mRNA) levels in the UUO kidney. In situ hybridization localized Par2 mRNA expression to tubular epithelial cells in normal kidney, with a marked increase in Par2 mRNA expression by tubular cells, including damaged tubular cells, in WT UUO kidney. Tubular damage (tubular dilation, increased KIM-1 and decreased α-Klotho expression) and tubular signalling (extracellular signal-regulated kinase phosphorylation) seen in WT UUO were not altered in Par2-/- UUO. In addition, macrophage infiltration, up-regulation of M1 (NOS2) and M2 (CD206) macrophage markers, and up-regulation of pro-inflammatory molecules (tumour necrosis factor, CCL2, interleukin-36α) in WT UUO kidney were unchanged in Par2-/- UUO. Finally, the accumulation of α-SMA+ myofibroblasts, deposition of collagen IV and expression of pro-fibrotic factors (CTGF, TGF-β1) were not different between WT and Par2-/- UUO mice.
Protease-activated receptor 2 expression is substantially up-regulated in tubular epithelial cells in the obstructed kidney, but this does not contribute to the development of tubular damage, renal inflammation or fibrosis.
蛋白酶激活受体 2（PAR2）已被牵连到肾炎症和纤维化的发展中。特别是，PAR2 在培养的肾小管上皮细胞中的激活诱导细胞外信号调节激酶信号和纤连蛋白、C-C 基序趋化因子配体 2（CCL2）和转化生长因子-β1（TGF-β1）的分泌，提示其在肾小管间质炎症和纤维化中发挥作用。我们在单侧输尿管梗阻（UUO）中测试了这一假说，其中持续的肾小管上皮细胞损伤驱动肾小管间质炎症和纤维化。
在 PAR2-/-和野生型（WT）同窝仔鼠的组（n = 9/10）中进行单侧输尿管梗阻手术，7 天后将其处死。非实验组的仔鼠为对照组。
WT 仔鼠的 UUO 肾脏中 Par2 信使 RNA（mRNA）水平增加了 5 倍。原位杂交将 Par2 mRNA 表达定位于正常肾脏的肾小管上皮细胞，在 WT UUO 肾脏中，包括受损的肾小管细胞在内的肾小管细胞中 Par2 mRNA 表达显著增加。WT UUO 中观察到的肾小管损伤（肾小管扩张、KIM-1 增加和α-Klotho 表达减少）和肾小管信号（细胞外信号调节激酶磷酸化）在 Par2-/-UUO 中没有改变。此外，巨噬细胞浸润、M1（NOS2）和 M2（CD206）巨噬细胞标志物的上调以及促炎分子（肿瘤坏死因子、CCL2、白细胞介素-36α）在 WT UUO 肾脏中的上调在 Par2-/-UUO 中也没有改变。最后，WT 和 Par2-/-UUO 仔鼠之间α-SMA+肌成纤维细胞的积累、胶原 IV 的沉积以及促纤维化因子（CTGF、TGF-β1）的表达没有差异。
在梗阻肾脏的肾小管上皮细胞中，蛋白酶激活受体 2 的表达显著上调，但这与肾小管损伤、肾炎症或纤维化的发展无关。
