Qi Chenyang, Hu Yuan, Zeng Mingyao, Chen Hongru, Shi Jiaoyu, Jue Hao, Zhao Zhonghua, Liu Jun, Zhang Zhigang, Xu Yanyong, Wu Huijuan
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Department of Nephrology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China.
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Life Sci. 2022 Dec 15;311(Pt B):121186. doi: 10.1016/j.lfs.2022.121186. Epub 2022 Nov 11.
The dedifferentiation of tubular epithelial cells has been identified as an important trigger of renal fibrosis. The Hippo pathway is a crucial regulator of cell proliferation and differentiation. In this study, we determined the role of Hippo proteins in tubular dedifferentiation in diabetic nephropathy (DN).
In this study, we measured dedifferentiation markers and Hippo proteins in db/db mice and high glucose treated tubular epithelial cells. Then, verteporfin and knockdown of large tumor suppressor kinase (LATS) 1 and 2 were performed to uncover therapeutic targets for DN.
Here, we found dedifferentiation and upregulated Hippo proteins in tubular epithelial cells in DN model both in vivo and in vitro. Both verteporfin and LATS knockdown could inhibit the tubular mesenchymal transition, but verteporfin showed broad inhibitory effect on Hippo proteins, especially nuclear YAP, and exacerbated podocyte loss of DN. LATS2 knockdown did not reverse the tubular E-Cadherin loss while it also induced podocyte apoptosis. Overall, intervention of LATS1 inhibited tubular dedifferentiation efficiently without affecting YAP and bringing podocyte apoptosis. Further mechanistic investigations revealed that the TGF-β1/Smad, instead of the YAP-TEAD-CTGF signaling, might be the underlying pathway through which verteporfin and LATS1 engaged in the tubular dedifferentiation.
In conclusion, verteporfin is not a suitable treatment for DN owing to evitable podocyte loss and apoptosis. Targeting LATS1 is a better choice worthy of further investigation for DN therapy.
肾小管上皮细胞去分化已被确认为肾纤维化的重要触发因素。Hippo信号通路是细胞增殖和分化的关键调节因子。在本研究中，我们确定了Hippo蛋白在糖尿病肾病（DN）肾小管去分化中的作用。
在本研究中，我们检测了db/db小鼠和高糖处理的肾小管上皮细胞中的去分化标志物和Hippo蛋白。然后，使用维替泊芬以及敲低大肿瘤抑制激酶（LATS）1和2，以揭示DN的治疗靶点。
在此，我们发现体内和体外DN模型的肾小管上皮细胞中均存在去分化和Hippo蛋白上调。维替泊芬和LATS敲低均可抑制肾小管间质转化，但维替泊芬对Hippo蛋白，尤其是核YAP具有广泛的抑制作用，并加剧了DN的足细胞丢失。LATS2敲低并未逆转肾小管E-钙黏蛋白的丢失，同时还诱导了足细胞凋亡。总体而言，LATS1的干预有效抑制了肾小管去分化，而不影响YAP且未导致足细胞凋亡。进一步的机制研究表明，TGF-β1/Smad信号通路而非YAP-TEAD-CTGF信号通路，可能是维替泊芬和LATS1参与肾小管去分化的潜在途径。
总之，由于不可避免的足细胞丢失和凋亡，维替泊芬不是DN的合适治疗方法。靶向LATS1是DN治疗中更值得进一步研究的更好选择。
