Exp Mol Med.  2012 Jan;44(1):45-51. 10.3858/emm.2012.44.1.004.

The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats

• Kim SH
• Jang YW
• Hwang P
• Kim HJ
• Han GY
• Kim CW

• KMID: 1120141
• DOI: http://doi.org/10.3858/emm.2012.44.1.004

Abstract

Diabetic nephropathy (DN) is a progressive kidney disease that is caused by injury to kidney glomeruli. Podocytes are glomerular epithelial cells and play critical roles in the glomerular filtration barrier. Recent studies have shown the importance of regulating the podocyte actin cytoskeleton in early DN. The phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, simultaneously regulates Rac1 and Cdc42, which destabilize the podocyte actin cytoskeleton during early DN. In this study, in order to evaluate the reno-protective effects of wortmannin in early DN by regulating Rac1 and Cdc42, streptozotocin (STZ)-induced proteinuric renal disease (SPRD) rats were treated with wortmannin. The albuminuria value of the SPRD group was 3.55 +/- 0.56 mg/day, whereas wortmannin group was 1.77 +/- 0.48 mg/day. Also, the albumin to creatinine ratio (ACR) value of the SPRD group was 53.08 +/- 10.82 mg/g, whereas wortmannin group was 20.27 +/- 6.41 mg/g. Changes in the expression level of nephrin, podocin and Rac1/Cdc42, which is related to actin cytoskeleton in podocytes, by wortmannin administration were confirmed by Western blotting. The expression levels of nephrin (79.66 +/- 0.02), podocin (87.81 +/- 0.03) and Rac1/Cdc42 (86.12 +/- 0.02) in the wortmannin group were higher than the expression levels of nephrin (55.32 +/- 0.03), podocin (53.40 +/- 0.06) and Rac1/Cdc42 (54.05 +/- 0.04) in the SPRD group. In addition, expression and localization of nephrin, podocin and desmin were confirmed by immunofluorescence. In summary, we found for the first time that wortmannin has a reno-protective effect on SPRD rats during the early DN. The beneficial effects of wortmannin in SPRD rats indicate that this compound could be used to delay the progression of the disease during the early DN stage.

Keyword

albuminuria; diabetic nephropathies; nephrin; podocin; podocytes; wortmannin

MeSH Terms

Albumins/metabolism
Androstadienes/*administration & dosage/pharmacology
Animals
Creatinine/blood
Desmin/genetics/metabolism
Diabetes Mellitus, Experimental/*drug therapy/metabolism/pathology
Diabetic Nephropathies/*drug therapy/metabolism/pathology
Disease Models, Animal
Humans
Intracellular Signaling Peptides and Proteins/genetics/metabolism
Kidney/*pathology
Membrane Proteins/genetics/metabolism
Phosphatidylinositol 3-Kinases/*antagonists & inhibitors
Podocytes/*drug effects/metabolism/pathology
Rats
Rats, Inbred Strains
cdc42 GTP-Binding Protein/genetics/metabolism
rac1 GTP-Binding Protein/genetics/metabolism