Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy.
Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy.
复制标题
DOI：
10.1016/j.jdiacomp.2014.05.010
复制
发表时间：
2014-09
影响因子：
3
通讯作者：
Nishiyama A
中科院分区：
文献类型：
--
作者：
Kitada K;Nakano D;Ohsaki H;Hitomi H;Minamino T;Yatabe J;Felder RA;Mori H;Masaki T;Kobori H;Nishiyama A
据报道，糖尿病肾病患者的肾细胞是衰老的。然而，调节糖尿病肾脏细胞衰老的机制仍然未知。在本研究中，我们评估了高糖对链脲佐菌素（STZ）诱导的糖尿病小鼠肾细胞衰老的贡献。非糖尿病和链脲佐菌素（STZ，10 mg/kg/天，持续7天，i. p.）本研究使用诱导的1型糖尿病C57 BL/6 J小鼠和培养的人近端肾小管细胞。在STZ注射后4周，高血压显著增加了肾脏p21的表达，但没有增加其他CDK抑制剂如p16和p27的表达。这些变化伴随着肾小管上皮细胞中衰老相关β-半乳糖苷酶染色的增加。维持正常血糖或轻度低血糖的胰岛素剂量抑制STZ引起的变化。胰岛素不影响非糖尿病小鼠的衰老标志物。暴露于25 mmol/L，但不是8 mmol/L，葡萄糖培养基培养的人近端肾小管细胞的衰老标志物的表达增加，这是抑制敲低p21或钠葡萄糖协同转运蛋白（SGLT）2。这些结果表明，高血糖症通过SGLT 2和p21依赖性途径引起1型糖尿病肾脏中的肾小管衰老。
Kidney cells in patients with diabetic nephropathy are reported to be senescent. However, the mechanisms that regulate cellular senescence in the diabetic kidney are still unknown. In the present study, we evaluated the contribution of high glucose to renal cell senescence in streptozotocin (STZ)-induced diabetic mice. Non-diabetic and streptozotocin (STZ, 10 mg kg–1 day–1 for 7 days, i.p.)-induced type 1 diabetic C57BL/6 J mice and cultured human proximal tubular cells were used in this study. Hyperglycemia dramatically increased the renal expression of p21 but not other CDK inhibitors such as p16 and p27 at 4 weeks after STZ injection. These changes were accompanied by an increase in senescence-associated β-galactosidase staining in tubular epithelial cells. Administration of insulin at doses that maintained normoglycemia or mild hypoglycemia suppressed the changes induced by STZ. Insulin did not affect the senescent markers in non-diabetic mice. Exposure of cultured human proximal tubular cells to 25 mmol/L, but not 8 mmol/L, glucose medium increased the expression of senescence markers, which was suppressed by knock-down of p21 or sodium glucose cotransporter (SGLT) 2. These results suggest that hyperglycemia causes tubular senescence via a SGLT2- and p21-dependent pathway in the type 1 diabetic kidney.
登录
查看更多内容
影响因子：
37.8
作者：
Kunieda, Takeshige;Minamino, Tohru;Komuro, Issei
通讯作者：
Komuro, Issei
影响因子：
3.7
作者：
Mortuza R;Chen S;Feng B;Sen S;Chakrabarti S
通讯作者：
Chakrabarti S
影响因子：
19.6
作者：
Al-Douahji, M;Brugarolas, J;Shankland, SJ
通讯作者：
Shankland, SJ
影响因子：
6.7
作者：
Pfister, M.;Whaley, J. M.;List, J. F.
通讯作者：
List, J. F.
影响因子：
3.2
作者：
Hitomi, Hirofumi;Kaifu, Kumiko;Fujita, Yoshiko;Sofue, Tadashi;Nakano, Daisuke;Moriwaki, Kumiko;Hara, Taiga;Kiyomoto, Hideyasu;Kohno, Masakazu;Kobori, Hiroyuki;Nishiyama, Akira
通讯作者：
Nishiyama, Akira