Effect of all-trans retinoic acid on renal expressions of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rats with glomerulosclerosis

Abstract

In kidney injury the accumulation of extracellular matrix (ECM) plays an important role and precedes the development of glomerulosclerosis (GS). There is great interest in agents that may interfere with such accumulation of ECM. Therefore, a rat model of GS was established to investigate the effect of all-trans retinoic acid (ATRA) on the renal expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Eighty Wistar rats were randomly divided into four groups: sham operation group (SHO), GS model group without treatment (GS), GS model group treated with benazepril (GB) and GS model group treated with ATRA (GA), n = 20, respectively. The disease was established in the GS rats by uninephrectomy and adriamycin (5 mg/kg) injection through the tail vein. Serum creatinine (Scr), blood urea nitrogen (BUN) and urine protein (Upro) were measured. Renal abnormality was evaluated at the end of 12 weeks. Immunohistochemical analysis was performed on renal tissue to detect the expression of collagen IV (Col-IV), fibronectin (FN), MMP-2, MMP-9 and TIMP-1 protein. MMP-2 and MMP-9 activity was detected by gelatin zymography. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was used to detect the expression of MMP-2, MMP-9, and TIMP-1 mRNA. In comparison with group GS, group GA and group GB exhibited levels of BUN and 24 h urinary protein and a glomerulosclerosis index (GSI) that were significantly reduced (P < 0.05); the level of Scr in group GA was reduced too (P < 0.05). ATRA and benazepril also significantly down-regulated Col-IV, FN expression and TIMP-1 expression (protein and mRNA) (P < 0.05). In contrast, the expressions of MMP-2, MMP-9 mRNA and protein, and activity in groups GA and GB were enhanced (P < 0.05). However, there were no significant differences in MMP-2, MMP-9 mRNA and protein expression, or activity, between the ATRA and GB groups (P > 0.05). In conclusion, ATRA may protect renal function and step down the progression of GS by reducing the expression of TIMP-1, enhancing the expression and activity of MMP-2 and MMP-9, and regulating the ratio of MMPs/TIMPs to dynamic balance, so as to reduce the accumulation of ECM.

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Abbreviations

ECM:

extracellular matrix

GS:

glomerulosclerosis

ATRA:

all-trans retinoic acid

MMP-2:

matrix metalloproteinase-2

MMP-9:

matrix metalloproteinase-9

TIMP-1:

tissue inhibitor of metalloproteinase-1

SHO:

sham operation group

GS:

GS model group without treatment

GB:

GS model group treated with benazepril

GA:

GS model group treated with ATRA

Scr:

serum creatinine

BUN:

blood urea nitrogen

Upro:

urine protein

Col-IV:

collagen IV

FN:

fibronectin

Real-time RT-PCR:

real-time reverse transcription polymerase chain reaction

MMPs:

matrix metalloproteinases

TIMPs:

tissue inhibitor of metalloproteinases

ADR:

adriamycin

GSI:

glomerulosclerosis index

H&E:

hematoxylin and eosin

BCA:

bicinchoninic acid

SDS:

sodium dodecylsulfate

Ct:

threshold cycle

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Acknowledgments

This study was supported by the Natural Science Foundation of the Guangxi Zhuang Autonomous Region (no. 0640103).

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Correspondence to Yuan-Han Qin.

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Qin, YH., Lei, FY., Hu, P. et al. Effect of all-trans retinoic acid on renal expressions of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rats with glomerulosclerosis. Pediatr Nephrol 24, 1477–1486 (2009). https://doi.org/10.1007/s00467-009-1166-1

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Keywords

  • All-trans retinoic acid
  • Matrix metalloproteinase
  • Tissue inhibitor of metalloproteinase
  • Extracellular matrix
  • Glomerulosclerosis