Summary.
Michael Brownlee has proposed a ‘Unifying Mechanism’ of hyperglycemia-induced damage in diabetes mellitus. At the crux of this hypothesis is the generation of reactive oxygen species (ROS), and their impact on glycolytic pathways.
Diabetes is the leading cause of chronic kidney failure. In the early phase of diabetes, prior to establishment of proteinuria or fibrosis, comes kidney growth and hyperfiltration. This early growth phase consists of an early period of hyperplasia followed by hypertrophy. Hypertrophy also contributes to cellular oxidative stress, and may precede the ROS perturbation of glycolytic pathways described in the Brownlee proposal. This increase in growth promotes hyperfiltration, and along with the hypertrophic phenotype appears required for hyperglycemia-induced cell damage and the progression of downstream diabetic complications. Here we will evaluate this growth phenomenon in the context of diabetes mellitus.
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Abbreviations
- AGE:
-
advanced glycation end products
- Ang II:
-
angiotensin II
- APR:
-
absolute proximal reabsorption
- 4E-BP1:
-
eIF-4E binding protein-1
- BrdU:
-
5-bromodeoxyuridine
- CKI:
-
cyclin dependent kinase inhibitor
- DAG:
-
diacylglycerol
- DFMO:
-
difluoromethylornithine
- ECM:
-
extracellular matrix
- EGF:
-
epidermal growth factor
- eIF-4E:
-
eukaryotic initiation factor 4E
- EMT:
-
epithelial-to-mesenchymal transition
- ERK1,2:
-
extracellular signal-regulated protein kinases
- ESRD:
-
end-stage renal disease
- FGF:
-
fibroblast growth factor
- FPR:
-
fractional proximal reabsorption
- GAPDH:
-
glyceraldehyde-3 phosphate dehydrogenase
- GFR:
-
glomerular filtration rate
- HGF:
-
hepatocyte growth factor
- IGF-1:
-
insulin-like growth factor
- MAPK:
-
mitogen-activated protein kinases
- MnSOD:
-
manganese superoxide dismutase
- mTOR:
-
mammalian target of rapamycin
- NF-κB:
-
nuclear factor kappa B
- ODC:
-
ornithine decarboxylase
- p27:
-
p27KIP1
- p27+/+:
-
p27KIP1 wild type mice
- p27−/−:
-
p27KIP1 deficient mice
- PAI-1:
-
plasminogen activator inhibitor-1
- PCNA:
-
proliferating cell nuclear antigen
- PDGF:
-
platelet-derived growth factor
- PKC:
-
protein kinase C
- RAGE:
-
receptor of advanced glycation end products
- ROS:
-
reactive oxygen species
- STZ:
-
streptozotocin
- TGF-β:
-
transforming growth factor-beta
- TGF:
-
tubuloglomerular feedback
- UCP-1:
-
uncoupling protein-1
- VEGF:
-
vascular endothelial growth factor
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Satriano, J. Kidney growth, hypertrophy and the unifying mechanism of diabetic complications. Amino Acids 33, 331–339 (2007). https://doi.org/10.1007/s00726-007-0529-9
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DOI: https://doi.org/10.1007/s00726-007-0529-9