Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension.
OBJECTIVE
The location of nephrin has been identified as the slit-diaphragm of the glomerular podocyte. Recent evidence suggests that nephrin could play a key role in the function of the glomerular filtration barrier and the development of proteinuria but its status in long-term diabetes is still not understood. We studied the expression of nephrin in a hypertensive model of diabetic nephropathy and investigated the potential influence of angiotensin II blockade on nephrin gene and protein expression.


METHODS
Streptozotocin-diabetic spontaneously hypertensive rats were given either no treatment or the angiotensin II antagonist, irbesartan, at a dose of 15 mg/kg per day by gavage for 32 weeks. Non-diabetic spontaneously hypertensive rats were used as a control group. Real time RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of nephrin.


RESULTS
Diabetic spontaneously hypertensive rats developed albuminuria and had a reduction in both gene and protein expression of nephrin when compared with control rats. Irbesartan treatment prevented the development of albuminuria and completely abrogated the down regulation of nephrin in diabetic rats.


CONCLUSIONS
Long-term diabetes in spontaneously hypertensive rats is associated with a reduction in both gene and protein expression of nephrin within the kidney. These changes in nephrin levels were completely prevented by angiotensin II antagonist treatment, suggesting a potential novel mechanism to explain the antiproteinuric effect of agents which interrupt the renin-angiotensin system.
Bonnet
F
F
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg West, Victoria, Australia.
Cooper
M E
ME
Kawachi
H
H
Allen
T J
TJ
Boner
G
G
Cao
Z
Z
D000419:Albuminuria / Q000517:prevention & control; D000704:Analysis of Variance; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy*; D000077405:Irbesartan; D008297:Male; D008565:Membrane Proteins; D015345:Oligonucleotide Probes; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D015345:Oligonucleotide Probes; D011506:Proteins; D013777:Tetrazoles; C113267:nephrin; D000077405:Irbesartan