The KCa3.1 blocker TRAM34 reverses renal damage in a mouse model of established diabetic nephropathy

Autor: Xin-Ming Chen, Carol A. Pollock, Chunling Huang, Yongli Zhao, Hao Yi, Ling Zhang, Jason Chen, Ying Shi
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Cell signaling
030232 urology & nephrology
lcsh:Medicine
Pharmacology
Signal transduction
Pathology and Laboratory Medicine
Kidney
Biochemistry
Diabetic nephropathy
Random Allocation
0302 clinical medicine
Endocrinology
Fibrosis
Medicine and Health Sciences
Diabetic Nephropathies
lcsh:Science
Immune Response
Mice
Knockout
Multidisciplinary
Signaling cascades
Heart
Animal Models
Intermediate-Conductance Calcium-Activated Potassium Channels
3. Good health
Extracellular Matrix
medicine.anatomical_structure
Experimental Organism Systems
Liver
medicine.symptom
Anatomy
Cellular Structures and Organelles
medicine.drug
Research Article
Cell biology
Nitric Oxide Synthase Type III
Endocrine Disorders
Immunology
Mouse Models
Research and Analysis Methods
Collagen Type I
Diabetes Mellitus
Experimental
03 medical and health sciences
Model Organisms
Signs and Symptoms
Diagnostic Medicine
Diabetes mellitus
medicine
Diabetes Mellitus
Potassium Channel Blockers
Albuminuria
Animals
Hypoglycemic Agents
Inflammation
business.industry
Myocardium
lcsh:R
Kidney metabolism
Biology and Life Sciences
Proteins
Kidneys
Renal System
medicine.disease
Streptozotocin
Fibronectins
030104 developmental biology
TGF-beta signaling cascade
Metabolic Disorders
Pyrazoles
lcsh:Q
business
Collagens
Spleen
Kidney disease
Developmental Biology
Zdroj: PLoS ONE
PLoS ONE, Vol 13, Iss 2, p e0192800 (2018)
ISSN: 1932-6203
Popis: Despite optimal control of hyperglycaemia, hypertension, and dyslipidaemia, the number of patients with diabetic nephropathy (DN) continues to grow. Strategies to target various signaling pathways to prevent DN have been intensively investigated in animal models and many have been proved to be promising. However, targeting these pathways once kidney disease is established, remain unsatisfactory. The clinical scenario is that patients with diabetes mellitus often present with established kidney damage and need effective treatments to repair and reverse the kidney damage. In this studies, eNOS-/- mice were administered with streptozotocin to induce diabetes. At 24 weeks, at which time we have previously demonstrated albuminuria and pathological changes of diabetic nephropathy, mice were randomised to receive TRAM34 subcutaneously, a highly selective inhibitor of potassium channel KCa3.1 or DMSO (vehicle) for a further 14 weeks. Albuminuria was assessed, inflammatory markers (CD68, F4/80) and extracellular matrix deposition (type I collagen and fibronectin) in the kidneys were examined. The results clearly demonstrate that TRAM34 reduced albuminuria, decreased inflammatory markers and reversed extracellular matrix deposition in kidneys via inhibition of the TGF-β1 signaling pathway. These results indicate that KCa3.1 blockade effectively reverses established diabetic nephropathy in this rodent model and provides a basis for progressing to human studies.
Databáze: OpenAIRE
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