title: Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan. Electronic address: kento-k@med.kagawa-u.ac.jp.
authors.forename: Kento
authors.initials: K
authors.lastname: Kitada
authors.affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.affiliation: Faculty of Clinical Examination, Ehime Prefectural University Of Health Sciences, Ehime, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohsaki
authors.affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.affiliation: Department of Cardiovascular Biology and Medicine Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.affiliation: Department of Pharmacology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Yatabe
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
authors.affiliation: Department of Gastroenterology, Kagawa University, Kagawa, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Gastroenterology, Kagawa University, Kagawa, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
authors.affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018450:Disease Progression; D006943:Hyperglycemia / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology; D051297:Sodium-Glucose Transporter 2 / Q000502:physiology*; D013311:Streptozocin
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D013311:Streptozocin
keywords: Cellular senescence; Diabetic nephropathy; Insulin; Proximal tubular cells; Sodium glucose cotransporter 2; p21