Podocyte injury is suppressed by 1,25-dihydroxyvitamin D via modulation of transforming growth factor-beta 1/bone morphogenetic protein-7 signalling in puromycin aminonucleoside nephropathy rats.
1. Accumulating evidence suggests that vitamin D and its analogues are renoprotective. However, the precise mechanisms and the molecular targets by which active vitamin D exerts its beneficial effects remain obscure. The objective of the present study was to evaluate the effect of active vitamin D on rats with puromycin aminonucleoside (PAN) nephropathy, a model that is characterized by predominant podocyte injury. 2. The PAN nephropathy rats were created by a single intravenous injection of 100 mg/kg PAN. Changes in renal pathology and podocyte numbers were observed. Real-time polymerase chain reaction (PCR) was performed to examine mRNA expression of nephrin, transforming growth factor (TGF)-beta1 and bone morphogenetic protein (BMP)-7. Protein expression of nephrin, TGF-beta1, BMP-7 and p-Smad2/3 and p-Smad1/5/8 was examined by immunofluorescence, immunohistochemistry and western blotting, respectively. Rats were treated with 1,25(OH)(2)D(3) by gastric gavage at a dose of 2.5 microg/kg per day, starting 2 days before PAN injection and continuing throughout the experiment. 3. A single injection of PAN induced massive proteinuria and elevated serum creatinine on Day 7, both of which were significantly suppressed by 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). Immunofluorescence and real-time PCR of the podocyte-associated protein nephrin revealed reduced and discontinuous staining and this change was reversed by 1,25(OH)(2)D(3). In PAN nephropathy rats, TGF-beta1 and p-Smad2/3 expression was upregulated, whereas that of BMP-7 and p-Smad1/5/8 was downregulated. Treatment with 1,25(OH)(2)D(3) significantly restored BMP-7/Smad signalling while suppressing TGF-beta1/Smad signalling. 4. In conclusion, 1,25(OH)(2)D(3) can ameliorate podocyte damage and proteinuria induced by PAN. The beneficial effects of 1,25(OH)(2)D(3) on podocytes may be attributable, in part, to direct modulation of TGF-beta1/BMP-7 signalling.
Xiao
Hou-Qin
HQ
Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong, China.
Shi
Wei
W
Liu
Shuang-Xin
SX
Zhang
Bin
B
Xu
Li-Xia
LX
Liang
Xin-Ling
XL
Liang
Yong-Zheng
YZ
D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000502:physiology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D050199:Podocytes / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D011692:Puromycin Aminonucleoside / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D055419:Bone Morphogenetic Protein 7; D053773:Transforming Growth Factor beta1; D014807:Vitamin D; D011692:Puromycin Aminonucleoside; C097949:1,25-dihydroxyvitamin D