PMID- 8887271
OWN - NLM
STAT- MEDLINE
DCOM- 19970310
LR  - 20190725
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 50
IP  - 4
DP  - 1996 Oct
TI  - Interstitial inflammation and fibrosis in rats with diet-induced 
      hypercholesterolemia.
PG  - 1139-49
AB  - Abnormalities in lipid metabolism appear to play a pathogenic role in progressive 
      renal disease. To elucidate the cellular and molecular basis of renal 
      interstitial fibrosis in uninephrectomized rats with diet-induced 
      hypercholesterolemia, we fed experimental rats with standard rat chow 
      supplemented with 4% cholesterol and 1% cholic acid. Control rats were fed an 
      isocaloric diet. Groups of 7 control and 7 experimental rats were killed after 4, 
      8, and 12 weeks. Hypercholesterolemic rats developed albuminuria; serum 
      creatinine was elevated at 12 weeks. By 12 weeks numerous oil red O-positive 
      cells were present throughout the interstitium and to a lesser extent in tubules. 
      Total renal lipid-peroxidation products were significantly increased (172 +/- 15, 
      198 +/- 28, and 197 +/- 13 mmol malondialdehyde/kidney at 4, 8, and 12 weeks vs. 
      123 +/- 17, 144 +/- 6, and 125 +/- 10 mmol in controls). Immunostaining revealed 
      oxidatively modified lipoproteins within tubular and interstitial cells. The 
      interstitial disease was characterized by an interstitial infiltrate of 
      monocytes. Significant increases were detected in renal cortical mRNA levels for 
      monocyte chemoattractant protein-1 (MCP-1), osteopontin, and vascular cell 
      adhesion molecule-1 (VCAM-1), associated with changes in the pattern of 
      immunostaining for each encoded proteins. Total kidney collagen was significantly 
      increased at 12 weeks (9.8 +/- 0.9 mg/kidney vs. 7.8 +/- 0.9 mg in controls). At 
      12 weeks there was a significant increase in interstitial immunostaining for 
      collagen I, collagen III, collagen IV, fibronectin and tenascin. A significant 
      threefold increase in renal cortical mRNA levels for transforming growth factor 
      beta-1 (TGF-beta 1) at 4 and 12 weeks was associated with the appearance of 
      TGF-beta 1-positive interstitial cells. Renal matrix protein mRNA levels were 
      measured at 4, 8, and 12 weeks. The only statistically significant elevations 
      were procollagen alpha 1(I) and procollagen alpha 1(III) at weeks 8 and 12. In 
      contrast, renal cortical mRNA levels for the tissue inhibitor of 
      metalloproteinases-1 (TIMP-1) were significantly increased at 4, 8 and 12 weeks 
      (1.4 +/- 0.5, 2.7 +/- 0.9 and 2.7 +/- 1.4 arbitrary densitometric units, 
      respectively, vs. 1.0 +/- 0.4, 1.0 +/- 0.5 and 1.0 +/- 0.4 units for controls), 
      and urokinase-type plasminogen activator (muPA) mRNA levels were significantly 
      decreased at 4, 8, and 12 weeks (0.4 +/- 0.1 arbitrary densitometric units for 
      all three experimental groups vs. 1.0 +/- 0.4, 1.0 +/- 0.3, and 1.0 +/- 0.4 units 
      for the control groups). In summary, rats with diet-induced hypercholesterolemia 
      develop renal interstitial fibrosis over several weeks. Following the 
      accumulation of lipids within tubulointerstitial cells, interstitial nephritis 
      develops. The fibrotic phase is characterized by modest changes in matrix protein 
      mRNA levels, up-regulated TIMP-1, and down-regulated muPA levels, suggesting that 
      altered matrix degradation plays a role in the interstitial fibrogenesis in this 
      model.
FAU - Eddy, A A
AU  - Eddy AA
AD  - Hospital for Sick Children, Toronto, Ontario, Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Actins)
RN  - 0 (Biomarkers)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Cholesterol, Dietary)
RN  - 0 (Extracellular Matrix Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Vascular Cell Adhesion Molecule-1)
RN  - 63231-63-0 (RNA)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Biomarkers/analysis
MH  - Chemokine CCL2/metabolism
MH  - Cholesterol, Dietary
MH  - *Diet, Atherogenic
MH  - Extracellular Matrix Proteins/metabolism
MH  - Female
MH  - Fibrosis/etiology
MH  - Glycoproteins/metabolism
MH  - Hypercholesterolemia/etiology/*pathology
MH  - Kidney/*pathology
MH  - Lipid Metabolism
MH  - Monocytes/metabolism
MH  - Nephrectomy
MH  - Nephritis, Interstitial/*pathology
MH  - Protease Inhibitors/metabolism
MH  - RNA/analysis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Time Factors
MH  - Tissue Inhibitor of Metalloproteinases
MH  - Transforming Growth Factor beta/metabolism
MH  - Urokinase-Type Plasminogen Activator/metabolism
MH  - Vascular Cell Adhesion Molecule-1/metabolism
EDAT- 1996/10/01 00:00
MHDA- 1996/10/01 00:01
CRDT- 1996/10/01 00:00
PHST- 1996/10/01 00:00 [pubmed]
PHST- 1996/10/01 00:01 [medline]
PHST- 1996/10/01 00:00 [entrez]
AID - S0085-2538(15)59715-9 [pii]
AID - 10.1038/ki.1996.421 [doi]
PST - ppublish
SO  - Kidney Int. 1996 Oct;50(4):1139-49. doi: 10.1038/ki.1996.421.