Combined effects of moderately elevated blood glucose and locally produced TGF-beta1 on glomerular morphology and renal collagen production.
BACKGROUND
There is a correlation between renal graft rejection and blood glucose (BG) levels. Furthermore, diabetic patients may develop non-diabetic renal diseases, which in some circumstances progress rapidly. Since transforming growth factor-beta1 (TGF-beta) levels are elevated in many renal diseases, the accelerated progression may be due to interactions between glucose and locally produced TGF-beta1. Therefore, we investigated the effect of mild hyperglycaemia on glomerular morphology and collagen production in TGF-beta1 transgenic mice.


METHODS
To achieve BG concentrations of approximately 15 mmol/l in TGF-beta1 transgenic and non-transgenic mice, we used multiple streptozotocin (STZ) injections, and after 8 weeks, we measured the changes in glomerular morphology and total collagen content. We also analysed extracellular matrix (ECM) and protease mRNA levels using real-time polymerase chain reaction (PCR) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK) expression by immunohistochemistry.


RESULTS
Mild hyperglycaemia alone had no effect on glomerular structure or ECM deposition. Over-expression of TGF-beta1 increased basement membrane thickness (BMT) and the mesangial volume fraction. Furthermore, it augmented ECM, Matrix metalloproteinase-2 (MMP), MMP-9, plasminogen activator inhibitor-1 (PAI) and tissue inhibitor of metalloproteinase-1 (TIMP) gene expression and pERK1/2 immunostaining. Elevated BG in combination with TGF-beta1 resulted in enlargement of glomerular volume, total mesangial volume and renal collagen content. Moreover, high BG exaggerated TGF-beta1-induced changes in the BMT, MMP-2 and TIMP-1 expression and pERK1/2 staining.


CONCLUSIONS
Even moderate elevations in BG accelerate the progression of those kidney diseases in which TGF-beta1 is involved. This emphasizes the importance of strict BG control in renal transplant patients and diabetic patients with renal malfunctions unrelated to diabetes.
Krag
Søren
S
Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Aarhus C, Denmark. soeren.krag@ki.au.dk
Nyengaard
Jens R
JR
Wogensen
Lise
L
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D050533:Glomerular Basement Membrane / Q000187:drug effects / Q000648:ultrastructure; D005920:Glomerular Mesangium / Q000187:drug effects / Q000201:enzymology; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D000099222:betaIG-H3 Protein
D001786:Blood Glucose; D003094:Collagen; D016326:Extracellular Matrix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D010447:Peptide Hydrolases; D010750:Phosphoproteins; D011480:Protease Inhibitors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein