title: Targeting cellular drivers and counter-regulators of hyperglycaemia- and transforming growth factor-β1-associated profibrotic responses in diabetic kidney disease.
abstract: Diabetic kidney disease occurs in >30% of patients with type 2 diabetes mellitus and is characterized at source by a maladaptive response in the renal parenchyma to exposure to a glucotoxic-lipotoxic diabetic milieu that courses coincident with hypertension. The consequence of these maladaptive responses is progressive renal injury, which is exacerbated by the development of a chronic inflammatory infiltrate associated with the development of tubulointerstitial fibrosis. The evolution of tubulointerstitial fibrosis is correlated with the loss of functional renal mass and descent towards renal failure. Transforming growth factor-β1 (TGF-β1) is a recognized mediator of the profibrotic response of mesangial cells and renal tubular epithelial cells to hyperglycaemia. While euglycaemia remains the goal in the treatment of type 2 diabetes mellitus, the prevention, arrest and reversal of microvascular complications, such as diabetic kidney disease, may be assisted by pharmacological modulation of the effectors of glucotoxicity, such as TGF-β1. This review focuses on describing how, through reductionist in vitro experimentation focusing on TGF-β1-related responses to hyperglycaemia, we have identified induced in high glucose-1 (IHG-1), induced in high glucose-2 (IHG-2/Grem1) and the lipoxin-inducible microRNA let-7c as potential targets for harnessing new therapeutic approaches to limit the bioactivity of TGF-β1 in diabetic kidney disease.
authors.affiliation: Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland neil.docherty@ucd.ie.
authors.forename: Neil G
authors.initials: NG
authors.lastname: Docherty
authors.affiliation: Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Madeline
authors.initials: M
authors.lastname: Murphy
authors.affiliation: Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.affiliation: Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Brennan
authors.affiliation: Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015195:Drug Design; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism; D058990:Molecular Targeted Therapy; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; C486399:GREM1 protein, human; D007004:Hypoglycemic Agents; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D011506:Proteins; C532028:THG1L protein, human; D053773:Transforming Growth Factor beta1; C487931:mirnlet7 microRNA, human