Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse.
OBJECTIVE
Previous studies showed that genetic deletion or pharmacological blockade of the receptor for advanced glycation end products (RAGE) prevents the early structural changes in the glomerulus associated with diabetic nephropathy. To overcome limitations of mouse models that lack the progressive glomerulosclerosis observed in humans, we studied the contribution of RAGE to diabetic nephropathy in the OVE26 type 1 mouse, a model of progressive glomerulosclerosis and decline of renal function.


METHODS
We bred OVE26 mice with homozygous RAGE knockout (RKO) mice and examined structural changes associated with diabetic nephropathy and used inulin clearance studies and albumin:creatinine measurements to assess renal function. Transcriptional changes in the Tgf-beta1 and plasminogen activator inhibitor 1 gene products were measured to investigate mechanisms underlying accumulation of mesangial matrix in OVE26 mice.


RESULTS
Deletion of RAGE in OVE26 mice reduced nephromegaly, mesangial sclerosis, cast formation, glomerular basement membrane thickening, podocyte effacement, and albuminuria. The significant 29% reduction in glomerular filtration rate observed in OVE26 mice was completely prevented by deletion of RAGE. Increased transcription of the genes for plasminogen activator inhibitor 1, Tgf-beta1, Tgf-beta-induced, and alpha1-(IV) collagen observed in OVE26 renal cortex was significantly reduced in OVE26 RKO kidney cortex. ROCK1 activity was significantly lower in OVE26 RKO compared with OVE26 kidney cortex.


CONCLUSIONS
These data provide compelling evidence for critical roles for RAGE in the pathogenesis of diabetic nephropathy and suggest that strategies targeting RAGE in long-term diabetes may prevent loss of renal function.
Reiniger
Nina
N
1Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA. nr2207@columbia.edu
Lau
Kai
K
McCalla
Daren
D
Eby
Bonnie
B
Cheng
Bin
B
Lu
Yan
Y
Qu
Wu
W
Quadri
Nosirudeen
N
Ananthakrishnan
Radha
R
Furmansky
Maryana
M
Rosario
Rosa
R
Song
Fei
F
Rai
Vivek
V
Weinberg
Alan
A
Friedman
Richard
R
Ramasamy
Ravichandran
R
D'Agati
Vivette
V
Schmidt
Ann Marie
AM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002645:Chickens; D003928:Diabetic Nephropathies / Q000235:genetics / Q000517:prevention & control; D004195:Disease Models, Animal; D017353:Gene Deletion; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D006442:Glycated Hemoglobin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D011765:Pyruvaldehyde / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency*; D051437:Renal Insufficiency / Q000235:genetics / Q000517:prevention & control
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D011765:Pyruvaldehyde; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic