TP63 Is Significantly Upregulated in Diabetic Kidney

Int J Mol Sci. 2021 Apr 15;22(8):4070. doi: 10.3390/ijms22084070.

Abstract

The role of tumor protein 63 (TP63) in regulating insulin receptor substrate 1 (IRS-1) and other downstream signal proteins in diabetes has not been characterized. RNAs extracted from kidneys of diabetic mice (db/db) were sequenced to identify genes that are involved in kidney complications. RNA sequence analysis showed more than 4- to 6-fold increases in TP63 expression in the diabetic mice's kidneys, compared to wild-type mice at age 10 and 12 months old. In addition, the kidneys from diabetic mice showed significant increases in TP63 mRNA and protein expression compared to WT mice. Mouse proximal tubular cells exposed to high glucose (HG) for 48 h showed significant decreases in IRS-1 expression and increases in TP63, compared to cells grown in normal glucose (NG). When TP63 was downregulated by siRNA, significant increases in IRS-1 and activation of AMP-activated protein kinase (AMPK (p-AMPK-Th172)) occurred under NG and HG conditions. Moreover, activation of AMPK by pretreating the cells with AICAR resulted in significant downregulation of TP63 and increased IRS-1 expression. Ad-cDNA-mediated over-expression of tuberin resulted in significantly decreased TP63 levels and upregulation of IRS-1 expression. Furthermore, TP63 knockdown resulted in increased glucose uptake, whereas IRS-1 knockdown resulted in a decrease in the glucose uptake. Altogether, animal and cell culture data showed a potential role of TP63 as a new candidate gene involved in regulating IRS-1 that may be used as a new therapeutic target to prevent kidney complications in diabetes.

Keywords: IRS-1; TP63; diabetes; kidney.

MeSH terms

  • Adenylate Kinase / metabolism
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Blood Glucose / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / genetics
  • Diabetic Nephropathies / blood
  • Diabetic Nephropathies / genetics*
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Kidney Tubules, Proximal / pathology
  • Models, Biological
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ribonucleotides / pharmacology
  • Signal Transduction / drug effects
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Tuberous Sclerosis Complex 2 Protein / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics*

Substances

  • Blood Glucose
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • RNA, Messenger
  • Ribonucleotides
  • Trans-Activators
  • Trp63 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • Aminoimidazole Carboxamide
  • Adenylate Kinase
  • AICA ribonucleotide