TY - JOUR
T1 - Sodium depletion enhances fibrosis and the expression of TGF-β1 and matrix proteins in experimental chronic cyclosporine nephropathy
AU - Shihab, Fuad S.
AU - Andoh, Takeshi F.
AU - Tanner, Amie M.
AU - Bennett, William M.
N1 - Funding Information:
Supported in part by grants from the National Kidney Foundation of Utah and the Dialysis Research Foundation (F.S.S.) and by grants from the Oregon Health Sciences University Foundation and the Clinical Research Group of Oregon (W.M.B. and T.F.A.).
PY - 1997/7
Y1 - 1997/7
N2 - The major limitation to the clinical use of cyclosporine (CsA) is renal toxicity. In the past, the lack of an animal model of chronic CsA nephropathy has hampered the study of its pathogenesis. Rats given CsA and placed on a low sodium diet (LSD) develop a histology similar to human lesions of chronic CsA nephropathy, a phenomenon not observed in animals on a normal sodium diet (NSD). We have previously shown that transforming growth factor-β1 (TGF- β1) is involved in the CsA-induced renal fibrosis in rats on a LSD. We hypothesized that sodium depletion is critical to the increase in TGF-β1 expression, which, in turn, results in excessive matrix accumulation. Pair- fed rats were placed on a NSD or LSD, treated with CsA or vehicle, and killed at 7 or 28 days (N = 4 to 6 in each group). All rats achieved similar blood pressure control, and all CsA-treated rats achieved similar CsA blood levels. However, while CsA did not affect creatinine clearance in rats on a NSD, it lowered creatinine clearance in rats on a LSD (P < 0.01). Cyclosporine- induced tubulointerstitial fibrosis and arteriolopathy was observed at 28 days only in the rats on a LSD (P < 0.05). In addition, peripheral renin activity was increased only in the rats on a LSD (P < 0.01), while it remained normal in the rats on a NSD. In addition, CsA-treated rats on a LSD developed a progressive increase in the mRNA expression of TGF-β1 and the matrix proteins biglycan and type I collagen at 7 and 28 days. Most of the changes were seen at 28 days (P < 0.001 for TGF-β1, P < 0.01 for biglycan and type I collagen). On the other hand, CsA treatment in rats on a NSD did not affect the mRNA expression of TGF-β1 and matrix proteins. Most of the changes in the immunofluorescence deposition of the glycoproteins tenascin and fibronectin EDA+ were in the tubulointerstitium and vessels of the kidneys of rats on a LSD and were mostly significant at 28 days, in accordance with the characteristic histology of chronic CsA nephropathy. The mRNA expression of plasminogen activator inhibitor-1, a protease inhibitor involved in matrix degradation and stimulated by TGF-β1, was observed only in kidneys of rats on a LSD (P < 0.01). Since sodium depletion elevates peripheral renin activity, our experiments suggest a role for the renin- angiotensin system in the expression of TGF-β1 and matrix proteins in CsA- induced renal fibrosis of rats on a LSD.
AB - The major limitation to the clinical use of cyclosporine (CsA) is renal toxicity. In the past, the lack of an animal model of chronic CsA nephropathy has hampered the study of its pathogenesis. Rats given CsA and placed on a low sodium diet (LSD) develop a histology similar to human lesions of chronic CsA nephropathy, a phenomenon not observed in animals on a normal sodium diet (NSD). We have previously shown that transforming growth factor-β1 (TGF- β1) is involved in the CsA-induced renal fibrosis in rats on a LSD. We hypothesized that sodium depletion is critical to the increase in TGF-β1 expression, which, in turn, results in excessive matrix accumulation. Pair- fed rats were placed on a NSD or LSD, treated with CsA or vehicle, and killed at 7 or 28 days (N = 4 to 6 in each group). All rats achieved similar blood pressure control, and all CsA-treated rats achieved similar CsA blood levels. However, while CsA did not affect creatinine clearance in rats on a NSD, it lowered creatinine clearance in rats on a LSD (P < 0.01). Cyclosporine- induced tubulointerstitial fibrosis and arteriolopathy was observed at 28 days only in the rats on a LSD (P < 0.05). In addition, peripheral renin activity was increased only in the rats on a LSD (P < 0.01), while it remained normal in the rats on a NSD. In addition, CsA-treated rats on a LSD developed a progressive increase in the mRNA expression of TGF-β1 and the matrix proteins biglycan and type I collagen at 7 and 28 days. Most of the changes were seen at 28 days (P < 0.001 for TGF-β1, P < 0.01 for biglycan and type I collagen). On the other hand, CsA treatment in rats on a NSD did not affect the mRNA expression of TGF-β1 and matrix proteins. Most of the changes in the immunofluorescence deposition of the glycoproteins tenascin and fibronectin EDA+ were in the tubulointerstitium and vessels of the kidneys of rats on a LSD and were mostly significant at 28 days, in accordance with the characteristic histology of chronic CsA nephropathy. The mRNA expression of plasminogen activator inhibitor-1, a protease inhibitor involved in matrix degradation and stimulated by TGF-β1, was observed only in kidneys of rats on a LSD (P < 0.01). Since sodium depletion elevates peripheral renin activity, our experiments suggest a role for the renin- angiotensin system in the expression of TGF-β1 and matrix proteins in CsA- induced renal fibrosis of rats on a LSD.
KW - Chronic nephrotoxicity
KW - Collagen
KW - Cyclosporine
KW - Extracellular matrix
KW - Fibrosis
KW - Glycoprotein
KW - Plasminogen activator inhibitor-1
KW - Proteoglycan
KW - Rats
KW - Salt
KW - Transforming growth factor-β
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U2 - 10.1016/S0272-6386(97)90567-9
DO - 10.1016/S0272-6386(97)90567-9
M3 - Article
C2 - 9214404
AN - SCOPUS:0030745637
SN - 0272-6386
VL - 30
SP - 71
EP - 81
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 1
ER -