Background:Chronic psychological stress is a risk factor for kidney disease, including kidney dysfunction and hypertension. Lysosomal CatK (cathepsin K) participates in various human pathobiologies. We investigated the role of CatK in kidney remodeling and hypertension in response to 5/6 nephrectomy injury in mice with or without chronic stress.Methods:Male 7-week-old WT (wild type; CatK^+/+) and CatK-deficient (CatK^−/−) mice that were or were not subjected to chronic stress underwent 5/6 nephrectomy. At 8 weeks post-stress/surgery, the stress was observed to have accelerated injury-induced glomerulosclerosis, proteinuria, and blood pressure elevation.Results:Compared with the nonstressed mice, the stressed mice showed increased levels of TLR (Toll-like receptor)-2/4, p22^phox, gp91^phox, CatK, MMP (matrix metalloproteinase)-2/9, collagen type I and III genes, PPAR-γ (peroxisome proliferator-activated receptor-gamma), NLRP-3 (NOD-like receptor thermal protein domain associated protein 3), p21, p16, and cleaved caspase-8 proteins, podocyte foot process effacement, macrophage accumulation, apoptosis, and decreased levels of Bcl-2 (B cell lymphoma 2) and Sirt1, as well as decreased glomerular desmin expression in the kidneys. These harmful changes were retarded by the genetic or pharmacological inhibition of CatK. Consistently, CatK inhibition ameliorated 5/6 nephrectomy–related kidney injury and dysfunction. In mesangial cells, CatK silencing or overexpression, respectively, reduced or increased the PPAR-γ and cleaved caspase-8 protein levels, providing evidence and a mechanistic explanation of CatK’s involvement in PPAR-γ/caspase-8–mediated cell apoptosis in response to superoxide and stressed serum.Conclusions:These results demonstrate that CatK plays an essential role in kidney remodeling and hypertension in response to 5/6 nephrectomy or stress, possibly via a reduction of glomerular inflammation, apoptosis, and fibrosis, suggesting a novel therapeutic strategy for controlling kidney injury in mice under chronic psychological stress conditions.

中文翻译：

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组织蛋白酶 K 缺乏可预防有或无慢性应激小鼠对 5/6 肾切除术损伤的肾脏损伤和功能障碍

背景：慢性心理压力是肾病的危险因素，包括肾功能不全和高血压。溶酶体 CatK（组织蛋白酶 K）参与各种人类病理生物学。我们研究了 CatK 在肾脏重塑和高血压中对有或没有慢性应激的小鼠 5/6 肾切除术损伤的反应。方法：雄性 7 周龄 WT（野生型；CatK ^+/+）和 CatK 缺陷（ CatK ^-/- ) 遭受或未遭受慢性应激的小鼠接受了 5/6 肾切除术。在应激/手术后 8 周，观察到应激加速了损伤引起的肾小球硬化、蛋白尿和血压升高。结果：与非应激小鼠相比，应激小鼠的 TLR（Toll 样受体）水平升高-2/4, p22^phox , gp91 ^phox、CatK、MMP（基质金属蛋白酶）-2/9、I 型和 III 型胶原基因、PPAR-γ（过氧化物酶体增殖物激活受体-γ）、NLRP-3（NOD 样受体热蛋白结构域相关蛋白 3）、p21 、p16 和切割的 caspase-8 蛋白、足细胞足突消失、巨噬细胞积聚、细胞凋亡和 Bcl-2（B 细胞淋巴瘤 2）和 Sirt1 水平降低，以及肾脏中肾小球结蛋白表达降低。这些有害变化因 CatK 的遗传或药理学抑制而受到阻碍。一致地，CatK 抑制改善了 5/6 肾切除术相关的肾损伤和功能障碍。在系膜细胞中，CatK 沉默或过表达分别降低或增加 PPAR-γ 和切割的 caspase-8 蛋白水平，