1,25-Dihydroxyvitamin D(3) prevents puromycin aminonucleoside-induced apoptosis of glomerular podocytes by activating the phosphatidylinositol 3-kinase/Akt-signaling pathway.
BACKGROUND
Accumulating evidence suggests that vitamin D and its analogs reduce proteinuria and slow the decline in kidney function in chronic kidney disease. Given a rich literature identifying podocyte apoptosis as an early step in the pathophysiological progression to proteinuria and glomerulosclerosis, we hypothesized that vitamin D protects podocytes from undergoing apoptosis.


METHODS
A rat model of podocyte apoptosis was created by a single intravenous injection of 100 mg x kg(-1) puromycin aminonucleoside (PAN) and received either solvent or 1,25(OH)(2)D(3) treatment. Proteinuria, podocyte apoptosis, the expression of nephrin protein and mRNA, TGF-beta/Smad and phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway were evaluated, respectively.


RESULTS
PAN induced massive proteinuria, serum creatinine elevation and podocyte apoptosis in PAN nephropathy rats, which was associated with the loss of nephrin, an adhesion molecule specific for the glomerular slit and the reduced of p-Akt/Akt ratio. Moreover, PAN induced foot process retraction, redistribution of nephrin and the activation of TGF-beta/Smad-signaling pathway. Compared with PAN nephropathy rats, 1,25(OH)(2)D(3) significantly prevented loss of nephrin, foot process retraction and podocyte apoptosis by stimulating Akt phosphorylation and suppressing TGF-beta/Smad-signaling pathway.


CONCLUSIONS
1,25(OH)(2)D(3) reduced the PAN-induced podocyte apoptosis and loss of nephrin in PAN nephropathy rat. The anti-apoptotic effects of 1,25(OH)(2)D(3 )on podocytes may be partly attributable to activation of a PI3K/Akt survival pathway.
Xiao
Houqin
H
Division of Nephrology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong, PR China.
Shi
Wei
W
Liu
Shuangxin
S
Wang
Wenjian
W
Zhang
Bin
B
Zhang
Yong
Y
Xu
Lixia
L
Liang
Xinling
X
Liang
Yongzheng
Y
D000818:Animals; D017209:Apoptosis; D002117:Calcitriol / Q000378:metabolism*; D004789:Enzyme Activation; D007678:Kidney Glomerulus / Q000378:metabolism*; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011692:Puromycin Aminonucleoside / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D011692:Puromycin Aminonucleoside; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002117:Calcitriol