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Kidney growth, hypertrophy and the unifying mechanism of diabetic complications

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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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  1. Division of Nephrology-Hypertension, Department of Medicine, The Veterans Administration San Diego Healthcare System, University of California San Diego, San Diego, CA, USA

    J. Satriano

  2. The Stein Institute for Research on Aging, University of California, San Diego, CA, USA

    J. Satriano

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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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