Kento Kitada1, Daisuke Nakano2, Hiroyuki Ohsaki3, Hirofumi Hitomi2, Tohru Minamino4, Junichi Yatabe5, Robin A Felder6, Hirohito Mori7, Tsutomu Masaki7, Hiroyuki Kobori2, Akira Nishiyama2. 1. Department of Pharmacology, Kagawa University, Kagawa, Japan. Electronic address: kento-k@med.kagawa-u.ac.jp. 2. Department of Pharmacology, Kagawa University, Kagawa, Japan. 3. Faculty of Clinical Examination, Ehime Prefectural University Of Health Sciences, Ehime, Japan. 4. Department of Cardiovascular Biology and Medicine Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 5. Department of Pharmacology, Fukushima Medical University, Fukushima, Japan. 6. Department of Pathology, University of Virginia, Charlottesville, VA, USA. 7. Department of Gastroenterology, Kagawa University, Kagawa, Japan.
Abstract
AIMS: 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. METHODS: Non-diabetic and streptozotocin (STZ, 10mgkg(-1)day(-1) for 7days, i.p.)-induced type 1 diabetic C57BL/6J mice and cultured human proximal tubular cells were used in this study. RESULTS: Hyperglycemia dramatically increased the renal expression of p21 but not other CDK inhibitors such as p16 and p27 at 4weeks 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 25mmol/L, but not 8mmol/L, glucose medium increased the expression of senescence markers, which was suppressed by knock-down of p21 or sodium glucose cotransporter (SGLT) 2. CONCLUSIONS: These results suggest that hyperglycemia causes tubular senescence via a SGLT2- and p21-dependent pathway in the type 1 diabetic kidney.
AIMS: 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 diabeticmice. METHODS:Non-diabetic and streptozotocin (STZ, 10mgkg(-1)day(-1) for 7days, i.p.)-induced type 1 diabetic C57BL/6J mice and cultured human proximal tubular cells were used in this study. RESULTS:Hyperglycemia dramatically increased the renal expression of p21 but not other CDK inhibitors such as p16 and p27 at 4weeks 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-diabeticmice. Exposure of cultured human proximal tubular cells to 25mmol/L, but not 8mmol/L, glucose medium increased the expression of senescence markers, which was suppressed by knock-down of p21 or sodium glucose cotransporter (SGLT) 2. CONCLUSIONS: These results suggest that hyperglycemia causes tubular senescence via a SGLT2- and p21-dependent pathway in the type 1 diabetic kidney.
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