Wu Wenwen, Fu Ying, Li Honglin, Xiang Yu, Zeng Yuqing, Cai Juan, Dong Zheng
Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Second Xiangya Hospital at Central South University, Changsha, China.
Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia.
J Am Soc Nephrol. 2025 Mar 1;36(3):348-360. doi: 10.1681/ASN.0000000530. Epub 2024 Oct 24.
-acetylgalactosaminyltransferase-3 (GALNT3) was downregulated in both ischemic AKI and cisplatin nephrotoxicity. GALNT3 played a protective role in renal tubular cells, and its downregulation contributed to AKI. Mechanistically, GALNT3 protected kidney tubular cells at least partially through O-glycosylation of EGF receptor.
Damages to subcellular organelles, such as mitochondria and endoplasmic reticulum, are well recognized in tubular cell injury and death in AKI. However, the changes and involvement of Golgi apparatus are much less known. In this study, we report the regulation and role of -acetylgalactosaminyltransferase-3 (GALNT3), a key enzyme for protein glycosylation in Golgi apparatus, in AKI.
AKI was induced in mice by renal ischemia–reperfusion injury or cisplatin. , rat kidney proximal tubular cells were subjected to hypoxia/reoxygenation (H/R) injury. To determine the role of GALNT3, its specific inhibitor T3inh-1 was tested in mice, and the effects of GALNT3 overexpression as well as knockdown were examined in the rat renal proximal tubular cells. EGF receptor (EGFR) activation was induced by recombinant EGF or by overexpressing EGFR.
GALNT3 was significantly decreased in both and models of AKI induced by renal ischemia–reperfusion injury and cisplatin. T3Inh-1, a specific GALNT3 inhibitor, exacerbated ischemic AKI and suppressed tubular cell proliferation in mice. Moreover, knockdown of GALNT3 increased apoptosis during H/R treatment in rat renal proximal tubular cells, whereas overexpression of GALNT3 attenuated H/R-induced apoptosis, further supporting a protective role of GALNT3. Mechanistically, GALNT3 contributed to O-glycosylation of EGFR and associated EGFR signaling. Activation or overexpression of EGFR suppressed the proapoptotic effect of GALNT3 knockdown in H/R-treated rat renal proximal tubular cells.
GALNT3 protected kidney tubular cells in AKI at least partially through O-glycosylation of EGFR.
α-1,3-N-乙酰半乳糖胺基转移酶-3（GALNT3）在缺血性急性肾损伤（AKI）和顺铂肾毒性中均下调。GALNT3在肾小管细胞中发挥保护作用，其下调导致AKI。机制上，GALNT3至少部分通过对表皮生长因子受体（EGF受体）进行O-糖基化来保护肾小管细胞。
在AKI的肾小管细胞损伤和死亡中，线粒体和内质网等亚细胞器的损伤已得到充分认识。然而，高尔基体的变化及参与情况却鲜为人知。在本研究中，我们报告了高尔基体中蛋白质糖基化的关键酶α-1,3-N-乙酰半乳糖胺基转移酶-3（GALNT3）在AKI中的调控及作用。
通过肾脏缺血再灌注损伤或顺铂诱导小鼠发生AKI。对大鼠肾近端小管细胞进行缺氧/复氧（H/R）损伤。为确定GALNT3的作用，在小鼠中测试其特异性抑制剂T3inh-1，并在大鼠肾近端小管细胞中检测GALNT3过表达及敲低的效果。通过重组EGF或过表达EGFR诱导EGF受体（EGFR）激活。
在肾脏缺血再灌注损伤和顺铂诱导的AKI模型中，GALNT3均显著降低。GALNT3特异性抑制剂T3Inh-1加重了小鼠的缺血性AKI并抑制肾小管细胞增殖。此外，敲低GALNT3增加了大鼠肾近端小管细胞在H/R处理期间的凋亡，而过表达GALNT3减轻了H/R诱导的凋亡，进一步支持了GALNT3的保护作用。机制上，GALNT3促进了EGFR的O-糖基化及相关的EGFR信号传导。EGFR的激活或过表达抑制了GALNT3敲低在H/R处理的大鼠肾近端小管细胞中的促凋亡作用。
GALNT3至少部分通过对EGFR进行O-糖基化来保护AKI中的肾小管细胞。
