Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201600, China.
Laboratory of Nephropathy, Translational Medicine Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201620, China.
Int J Mol Sci. 2023 Oct 17;24(20):15258. doi: 10.3390/ijms242015258.
The Hippo pathway mediates renal maladaptive repair after acute kidney injury (AKI), which has been considered a driving force in the progression to chronic kidney disease (CKD). LATS2, a core kinase of the Hippo pathway, exerts non-Hippo-dependent functions in the regulation of the cell cycle and cell fate, providing new insights into AKI and further repair. However, its role remains unknown. Here, we utilized a proximal tubular conditional knockout mouse strain (-CKO) to evaluate the effect of LATS2 deficiency on ischemia/reperfusion-induced AKI-to-CKD transition. -CKO mice presented with more severe tubular maladaptive repair, inflammatory infiltration, interstitial fibrosis, and apoptosis following AKI. Importantly, we discovered that ablation caused the activation of p53, with increased levels of cellular apoptotic molecules (p21, Bax, and cleaved caspase-3), and decreased levels of anti-apoptotic molecules (Bcl-2 and Bcl-xL). Pifithirin-α (p53 inhibitor) effectively attenuated renal fibrosis, inflammation, and apoptosis in -CKO mice after AKI. Consistently, in vitro overexpression decreased p53, p21, Bax and cleaved caspase 3 expression after hypoxia/reoxygenation (H/R) treatment. Of note, the phosphorylation of MDM2, which promotes the ubiquitination degradation of p53, at site Ser186 was decreased in -CKO kidneys, but increased by overexpression in vitro. Therefore, LATS2 deficiency aggravated ischemia/reperfusion injury (IRI)-induced maladaptive repair via regulating the tubular MDM2-p53 axis in AKI-to-CKD transition.
Hippo 通路介导急性肾损伤 (AKI) 后的肾脏适应性修复，这被认为是慢性肾脏病 (CKD) 进展的驱动力。LATS2 是 Hippo 通路的核心激酶，在细胞周期和细胞命运的调节中发挥非 Hippo 依赖的功能，为 AKI 及进一步修复提供了新的见解。然而，其作用仍不清楚。在这里，我们利用近端肾小管条件性敲除小鼠品系 (-CKO) 来评估 LATS2 缺失对缺血/再灌注诱导的 AKI 向 CKD 转变的影响。-CKO 小鼠在 AKI 后表现出更严重的肾小管适应性修复、炎症浸润、间质纤维化和细胞凋亡。重要的是，我们发现缺失导致了 p53 的激活，细胞凋亡分子（p21、Bax 和 cleaved caspase-3）水平升高，抗凋亡分子（Bcl-2 和 Bcl-xL）水平降低。Pifithirin-α（p53 抑制剂）有效减轻了 AKI 后 -CKO 小鼠的肾纤维化、炎症和细胞凋亡。一致地，体外过表达降低了缺氧/复氧 (H/R) 处理后 p53、p21、Bax 和 cleaved caspase 3 的表达。值得注意的是，-CKO 肾脏中 MDM2 丝氨酸 186 位点的磷酸化（促进 p53 的泛素化降解）减少，但体外过表达增加。因此，LATS2 缺失通过调节 AKI 向 CKD 转变中的肾小管 MDM2-p53 轴加重缺血/再灌注损伤 (IRI) 诱导的适应性修复。
