Expression of the slit-diaphragm protein, nephrin, in experimental diabetic nephropathy: differing effects of anti-proteinuric therapies.
BACKGROUND
Mutations in the gene coding for the podocyte slit-pore membrane protein, nephrin, are responsible for the Finnish-type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti-proteinuric therapies.


METHODS
Nephrin gene expression and localization were examined in rats with streptozotocin-induced diabetes at 6 months duration (proteinuric phase) and at 7 days (pre-proteinuric phase). In addition, the effects of anti-proteinuric drug therapies were also assessed in long-term diabetic rats, treated with either the angiotensin-converting enzyme inhibitor perindopril, or the blocker of advanced glycation end-product formation, aminoguanidine. Nephrin expression was determined using quantitative real-time PCR and in situ hybridization.


RESULTS
When compared with control animals, nephrin expression was reduced in the late proteinuric phase (45% reduction vs controls, P<0.01) but not in the early, pre-proteinuric phase of experimental diabetic nephropathy. While ACE inhibition and aminoguanidine both reduced proteinuria, only the former attenuated the diabetes-associated reduction in nephrin expression.


CONCLUSIONS
These findings suggests that reduction in nephrin may be a determinant of glomerular hyperpermeability in diabetic nephropathy. Attenuation of these changes with ACE inhibition suggest that this mechanism may contribute to the anti-proteinuric effects of this, but not all classes of drug which reduce urinary protein in diabetic nephropathy.
Kelly
Darren J
DJ
University of Melbourne Department of Medicine at St Vincent's Hospital, Fitzroy, Victoria, Australia.
Aaltonen
Petri
P
Cox
Alison J
AJ
Rumble
Jon R
JR
Langham
Robyn
R
Panagiotopoulos
Sianna
S
Jerums
George
G
Holthöfer
Harry
H
Gilbert
Richard E
RE
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics*; D006146:Guanidines / Q000627:therapeutic use*; D017403:In Situ Hybridization; D008297:Male; D008565:Membrane Proteins; D009154:Mutation; D020913:Perindopril / Q000627:therapeutic use*; D011506:Proteins / Q000378:metabolism*; D011507:Proteinuria / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000806:Angiotensin-Converting Enzyme Inhibitors; D017931:DNA Primers; D006146:Guanidines; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; C113267:nephrin; C004479:pimagedine; D020913:Perindopril