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TGF-β1 expression and mesangial alterations in rat glomeruli of an experimental chronic nephrosis model

Year 2019, Volume: 43 Issue: 1, 6 - 12, 01.07.2019

Abstract

Objective: Puromycine aminonucleoside
nephrosis (PAN) is extensively used as an experimental model of proteinuria
following podocyte injury. In PAN animal models, nephrotic syndrome with
minimal change disease and focal segmental sclerosis-like nephritis is
demonstrated to be similar to that in human; however, the real mechanism of PAN
is not yet elucidated. Evidence shows that transforming growth factor-β1
(TGF-β1) plays a key via stimulating matrix protein synthesis of both
glomerular epithelial and mesangial cells. In this study, we aimed to examine
the relationship between TGF-β expression and accumulation in mesangial matrix
(MM) by the changes in renal function and ultrastructure alterations in renal
glomeruli of the chronic PAN induced rats.

Methods: Twelve male Wistar albino rats
were divided into two groups: control group (n=6), chronic group (n=6). All
data was statistically analyzed by One-way ANOVA Test.

Results: Proteinuria levels in the chronic
nephrosis groups were greater than the control (p<0.0025) whereas the levels
of serum albumin and creatinine clearances were progressively decreased
(p<0.05). TGF-β1 expression and MM were both significantly increased in PAN
group. Ultrastructural images of glomeruli of PAN showed apoptotic endothelium
and mesangial cells, interstitial collagen and macrophages in increased MM.







Conclusion: Our findings suggest that
chronic PAN application induces a nephrotic syndrome, leading to renal
impairment by TGF-β1 expression in glomeruli, increase in MM, formation of
abundant interstitial collagen, and migration of macrophages. We suggest that
chronic PAN progressively increases TGF-β1 expression and apoptosis following
expansion of mesangial matrix in the affected glomeruli. This study needs
further researches to determine the main source and signal pathway of TGF-β1
expression by double staining methods.

Cite this article as: Seçkin İ, Uzunalan M,
Ayaz Pekpak M, Köktürk S, Sönmez HA, Güngör ZB. TGF-β1 expression and mesangial
alterations in rat glomeruli of an experimental chronic nephrosis model.
Cerrahpasa Med J 2019; 43(1): 6-12.

References

  • 1. Krishnamurti U, Zhou B, Fan WW, Tsilibary E, Wayner E, Kim Y, et al. Puromycin aminonucleoside suppresses integrin expression in cultured glomerular epithelial cells. J Am Soc Nephrol 2001; 12: 758-66. 2. Sanwal V, Pandya M, Bhaskaran M, Franki N, Reddy K, et al. Puromycin aminonucleoside induces glomerular epithelial cell apoptosis. Exp Mol Pathol 2001; 70: 54-64. 3. Savill J, Mooney A, Hughes J. Apoptosis and renal scarring. Kidney Int Suppl 1996; 54: S14-7. 4. Makino H, Shikata K, Wieslander J, Wada J, Kashihara N, Yoshioka K, et al. Localization of fibril/microfibril and basement membrane collagens in diabetic glomerulosclerosis in type 2 diabetes. Diabet Med 1994; 11: 304-11. 5. Marinides GN, Groggel GC, Cohen AH, Border WA. Enalapril and low protein reverse chronic puromycin aminonucleoside nephropathy. Kidney Int 1990; 37: 749-57. 6. Raij L, Azar S, Keane W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int 1984; 26: 137-43. 7. Hill C, Flyvbjerg A, Grønbaek H, Petrik J, Hill DJ, Thomas CR, et al. The renal expression of transforming growth factor-β isoforms and their receptors in acute and chronic experimental diabetes in rats. Endocrinology 2000; 141: 1196-208. 8. Kihara I, Yaoita E, ,Yamamoto T. Cellular processes of glomerular adhesion in aged rats. Acta Medica et Biologica 1990; 38: 69-80. 9. Shimizu A, Kitamura H, Masuda Y, Ishizaki M, Sugisaki Y, Yamanaka N. Apoptosis in the repair process of experimental proliferative glomerulonephritis. Kidney Int 1995; 47: 114-21. 10. Morioka Y, Koike H, Ikezumi Y, Ito Y, Oyanagi A, Gejyo F, et al. Podocyte injuries exacerbate mesangial proliferative glomerulonephritis. Kidney Int 2001; 60: 2192-204. 11. Kaplan L. Pesce Al Clinical Chemistry Theory, Analysis and Correlation. St. Louis, Mo: CV Mosby Co, 1984. 1231. 12. Seckin I, Uzunalan M, Pekpak M, Kokturk S, Sonmez H, Oztürk Z, et al. Experimentally induced puromycine aminonucleoside nephrosis (PAN) in rats: evaluation of angiogenic protein platelet-derived endothelial cell growth factor (PD-ECGF) expression in glomeruli. J Biomed Sci 2012; 19: 24. 13. Powell H. Relationship between proteinuria and epithelial cell changes in minimal lesion glomerulopathy. Nephron 1976; 16: 310-7. 14. Davies M, Shewring L, Thomas G, Jenner L. Stimulation of proteoglycan (pg) synthesis in rat mesangial cells (rmc) in response to tumor necrosing factor (tnf). In kidney international 1989. 15. Okuda S, Languino LR, Ruoslahti E, Border WA. Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix. J Clin Invest 1990; 86: 453-62. 16. Border WA, Noble NA. Transforming growth factor β in tissue fibrosis. N Engl J Med 1994; 331: 1286-92. 17. Lafayette RA, Mayer G, Park SK, Meyer TW. Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 1992; 90: 766-71. 18. Pawluczyk IZ, Harris KP. Harris, Transforming growth factor-β suppresses macrophage-induced mesangial cell fibronectin expression. Kidney Int 2001; 60: 533-42. 19. Sharma R1, Khanna A, Sharma M, Savin VJ. Transforming growth factor-β1 increases albumin permeability of isolated rat glomeruli via hydroxyl radicals. Kidney Int 2000; 58: 131-6. 20. Akagi Y, Isaka Y, Arai M, Kaneko T, Takenaka M, Moriyama T, et al. Inhibition of TGF-β1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 1996; 50: 148-55. 21. Lee HS, Song CY. Differential role of mesangial cells and podocytes in TGF-beta-induced mesangial matrix synthesis in chronic glomerular disease. Histol Histopathol 2009; 24: 901-8. 22. Sandau K, Pfeilschifter J, Brüne B. Nitric oxide and superoxide induced p53 and Bax accumulation during mesangial cell apoptosis. Kidney Int 1997; 52: 378-86. 23. Johnson R, Yamabe H, Chen YP, Campbell C, Gordon K, Baker P, et al. Glomerular epithelial cells secrete a glomerular basement membrane-degrading metalloproteinase. J Am Soc Nephrol 1992; 2: 1388-97. 24. Johnson RJ, Lovett D. In vivo gene transfer, Koch’s postulates, and renal disease. J Clin Invest 1993; 92: 2568. 25. Shimizu A, Masuda Y, Kitamura H, Ishizaki M, Sugisaki Y, Yamanaka N. Apoptosis in progressive crescentic glomerulonephritis. Lab Invest 1996; 74: 941-51.

Deneysel Kronik Nefroz Modeli Sıçan Glomerüllerinde TGF-b1 Ekspresyonu ve Mezangiyal Değişiklikler

Year 2019, Volume: 43 Issue: 1, 6 - 12, 01.07.2019

Abstract

Amaç: Puromisin aminonükleozid nefroz
(PAN), proteinüri ile seyreden podosit yaralanması modeli olarak yaygın bir
şekilde kullanılmaktadır. Deneysel olarak uyarılmış PAN hayvan modellerinde,
minimal değişikliklere sahip insan nefrotik sendromu ve fokal segmental
glomerulosklerozdakine benzer histolojik değişiklikler gösterilmiş, ancak etki
mekanizması tam olarak anlaşılamamıştır. Yapılan çalışmalar, çoğu kronik böbrek
hasarlarında, ekstrasellüler matriks (ESM) birikiminin görüldüğü ve bu süreçte
transforming büyüme faktörü-β1 (TGF-β1)’in anahtar bir rol oynadığı gösterilmiştir.  Bu çalışmada biz, kronik PAN uyarılı sıçan
böbrek glomerüllerinde, TGF-β1 ekspresyonu ve mezangial matriks (MM) birikimi
arasındaki ilişkiyi, böbrek fonksiyonu ve ultrastrüktürel değişikliklerle
incelemeyi amaçladık.



Yöntemler: Bu çalışma için 12 erkek Wistar
albino sıçan iki gruba ayrıldı: kontrol grubu ve kronik grup (n=6). Bütün
veriler istatistiksel olarak One-way ANOVA testi ile analiz edildi.



Bulgular: Proteinüri seviyeleri kronik
nefroz grubunda kontrolden yüksek (p<0,0025), serum albümin ve kreatinin
klirens değerleri ise oldukça düşüktü (p<0,05). PAN nefrozlu sıçanların
glomerüllerinde, hem TGF-β1 ekspresyonu hem de MM birikimi belirgin şekilde
artmıştı. Kronik PAN grubunun glomerüllerinin ultrastrüktürel görüntülerinde
artmış MM içerisinde apoptotik endotel ve mezangial hücrelere, interstisyal
kollajene ve makrofajlara rastladık.



Sonuç: Bulgularımız, kronik PAN
uygulamasının böbrek fonksiyonlarında bozulma ile birlikte, glomerülde TGF-β1
ekspresyonu, MM artışına, interstisyal kollajen oluşumuna ve makrofajların
göçüne neden olan bir nefrotik sendromu indüklediğini düşündürmektedir. Bu
çalışma, ikili işaretlemelerle TGF-β1’in ana kaynağının ve TGF-β1 sinyal
yolaklarının belirlenmesi için daha ileri çalışmalara ihtiyaç duymaktadır.

Cite this article as: Seçkin İ, Uzunalan M,
Ayaz Pekpak M, Köktürk S, Sönmez HA, Güngör ZB. TGF-β1 expression and mesangial
alterations in rat glomeruli of an experimental chronic nephrosis model.
Cerrahpasa Med J 2019; 43(1): 6-12.

References

  • 1. Krishnamurti U, Zhou B, Fan WW, Tsilibary E, Wayner E, Kim Y, et al. Puromycin aminonucleoside suppresses integrin expression in cultured glomerular epithelial cells. J Am Soc Nephrol 2001; 12: 758-66. 2. Sanwal V, Pandya M, Bhaskaran M, Franki N, Reddy K, et al. Puromycin aminonucleoside induces glomerular epithelial cell apoptosis. Exp Mol Pathol 2001; 70: 54-64. 3. Savill J, Mooney A, Hughes J. Apoptosis and renal scarring. Kidney Int Suppl 1996; 54: S14-7. 4. Makino H, Shikata K, Wieslander J, Wada J, Kashihara N, Yoshioka K, et al. Localization of fibril/microfibril and basement membrane collagens in diabetic glomerulosclerosis in type 2 diabetes. Diabet Med 1994; 11: 304-11. 5. Marinides GN, Groggel GC, Cohen AH, Border WA. Enalapril and low protein reverse chronic puromycin aminonucleoside nephropathy. Kidney Int 1990; 37: 749-57. 6. Raij L, Azar S, Keane W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int 1984; 26: 137-43. 7. Hill C, Flyvbjerg A, Grønbaek H, Petrik J, Hill DJ, Thomas CR, et al. The renal expression of transforming growth factor-β isoforms and their receptors in acute and chronic experimental diabetes in rats. Endocrinology 2000; 141: 1196-208. 8. Kihara I, Yaoita E, ,Yamamoto T. Cellular processes of glomerular adhesion in aged rats. Acta Medica et Biologica 1990; 38: 69-80. 9. Shimizu A, Kitamura H, Masuda Y, Ishizaki M, Sugisaki Y, Yamanaka N. Apoptosis in the repair process of experimental proliferative glomerulonephritis. Kidney Int 1995; 47: 114-21. 10. Morioka Y, Koike H, Ikezumi Y, Ito Y, Oyanagi A, Gejyo F, et al. Podocyte injuries exacerbate mesangial proliferative glomerulonephritis. Kidney Int 2001; 60: 2192-204. 11. Kaplan L. Pesce Al Clinical Chemistry Theory, Analysis and Correlation. St. Louis, Mo: CV Mosby Co, 1984. 1231. 12. Seckin I, Uzunalan M, Pekpak M, Kokturk S, Sonmez H, Oztürk Z, et al. Experimentally induced puromycine aminonucleoside nephrosis (PAN) in rats: evaluation of angiogenic protein platelet-derived endothelial cell growth factor (PD-ECGF) expression in glomeruli. J Biomed Sci 2012; 19: 24. 13. Powell H. Relationship between proteinuria and epithelial cell changes in minimal lesion glomerulopathy. Nephron 1976; 16: 310-7. 14. Davies M, Shewring L, Thomas G, Jenner L. Stimulation of proteoglycan (pg) synthesis in rat mesangial cells (rmc) in response to tumor necrosing factor (tnf). In kidney international 1989. 15. Okuda S, Languino LR, Ruoslahti E, Border WA. Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix. J Clin Invest 1990; 86: 453-62. 16. Border WA, Noble NA. Transforming growth factor β in tissue fibrosis. N Engl J Med 1994; 331: 1286-92. 17. Lafayette RA, Mayer G, Park SK, Meyer TW. Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 1992; 90: 766-71. 18. Pawluczyk IZ, Harris KP. Harris, Transforming growth factor-β suppresses macrophage-induced mesangial cell fibronectin expression. Kidney Int 2001; 60: 533-42. 19. Sharma R1, Khanna A, Sharma M, Savin VJ. Transforming growth factor-β1 increases albumin permeability of isolated rat glomeruli via hydroxyl radicals. Kidney Int 2000; 58: 131-6. 20. Akagi Y, Isaka Y, Arai M, Kaneko T, Takenaka M, Moriyama T, et al. Inhibition of TGF-β1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 1996; 50: 148-55. 21. Lee HS, Song CY. Differential role of mesangial cells and podocytes in TGF-beta-induced mesangial matrix synthesis in chronic glomerular disease. Histol Histopathol 2009; 24: 901-8. 22. Sandau K, Pfeilschifter J, Brüne B. Nitric oxide and superoxide induced p53 and Bax accumulation during mesangial cell apoptosis. Kidney Int 1997; 52: 378-86. 23. Johnson R, Yamabe H, Chen YP, Campbell C, Gordon K, Baker P, et al. Glomerular epithelial cells secrete a glomerular basement membrane-degrading metalloproteinase. J Am Soc Nephrol 1992; 2: 1388-97. 24. Johnson RJ, Lovett D. In vivo gene transfer, Koch’s postulates, and renal disease. J Clin Invest 1993; 92: 2568. 25. Shimizu A, Masuda Y, Kitamura H, Ishizaki M, Sugisaki Y, Yamanaka N. Apoptosis in progressive crescentic glomerulonephritis. Lab Invest 1996; 74: 941-51.
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Details

Primary Language Turkish
Subjects Clinical Sciences
Journal Section Araştırmalar
Authors

İsmail Seçkin This is me

Mümin Uzunalan This is me

Meltem Ayaz Pekyak This is me

Sibel Köktürk This is me

Hüseyin Avni Sönmez This is me

Zeynep Banu Güngör This is me

Elif Yaprak Saraç This is me

Aslı Emincik This is me

Sibel Demirci Delipınar This is me

Publication Date July 1, 2019
Published in Issue Year 2019 Volume: 43 Issue: 1

Cite

APA Seçkin, İ., Uzunalan, M., Ayaz Pekyak, M., Köktürk, S., et al. (2019). Deneysel Kronik Nefroz Modeli Sıçan Glomerüllerinde TGF-b1 Ekspresyonu ve Mezangiyal Değişiklikler. Cerrahpaşa Tıp Dergisi, 43(1), 6-12.
AMA Seçkin İ, Uzunalan M, Ayaz Pekyak M, Köktürk S, Sönmez HA, Güngör ZB, Saraç EY, Emincik A, Demirci Delipınar S. Deneysel Kronik Nefroz Modeli Sıçan Glomerüllerinde TGF-b1 Ekspresyonu ve Mezangiyal Değişiklikler. Cerrahpaşa Tıp Dergisi. July 2019;43(1):6-12.
Chicago Seçkin, İsmail, Mümin Uzunalan, Meltem Ayaz Pekyak, Sibel Köktürk, Hüseyin Avni Sönmez, Zeynep Banu Güngör, Elif Yaprak Saraç, Aslı Emincik, and Sibel Demirci Delipınar. “Deneysel Kronik Nefroz Modeli Sıçan Glomerüllerinde TGF-B1 Ekspresyonu Ve Mezangiyal Değişiklikler”. Cerrahpaşa Tıp Dergisi 43, no. 1 (July 2019): 6-12.
EndNote Seçkin İ, Uzunalan M, Ayaz Pekyak M, Köktürk S, Sönmez HA, Güngör ZB, Saraç EY, Emincik A, Demirci Delipınar S (July 1, 2019) Deneysel Kronik Nefroz Modeli Sıçan Glomerüllerinde TGF-b1 Ekspresyonu ve Mezangiyal Değişiklikler. Cerrahpaşa Tıp Dergisi 43 1 6–12.
IEEE İ. Seçkin, M. Uzunalan, M. Ayaz Pekyak, S. Köktürk, H. A. Sönmez, Z. B. Güngör, E. Y. Saraç, A. Emincik, and S. Demirci Delipınar, “Deneysel Kronik Nefroz Modeli Sıçan Glomerüllerinde TGF-b1 Ekspresyonu ve Mezangiyal Değişiklikler”, Cerrahpaşa Tıp Dergisi, vol. 43, no. 1, pp. 6–12, 2019.
ISNAD Seçkin, İsmail et al. “Deneysel Kronik Nefroz Modeli Sıçan Glomerüllerinde TGF-B1 Ekspresyonu Ve Mezangiyal Değişiklikler”. Cerrahpaşa Tıp Dergisi 43/1 (July 2019), 6-12.
JAMA Seçkin İ, Uzunalan M, Ayaz Pekyak M, Köktürk S, Sönmez HA, Güngör ZB, Saraç EY, Emincik A, Demirci Delipınar S. Deneysel Kronik Nefroz Modeli Sıçan Glomerüllerinde TGF-b1 Ekspresyonu ve Mezangiyal Değişiklikler. Cerrahpaşa Tıp Dergisi. 2019;43:6–12.
MLA Seçkin, İsmail et al. “Deneysel Kronik Nefroz Modeli Sıçan Glomerüllerinde TGF-B1 Ekspresyonu Ve Mezangiyal Değişiklikler”. Cerrahpaşa Tıp Dergisi, vol. 43, no. 1, 2019, pp. 6-12.
Vancouver Seçkin İ, Uzunalan M, Ayaz Pekyak M, Köktürk S, Sönmez HA, Güngör ZB, Saraç EY, Emincik A, Demirci Delipınar S. Deneysel Kronik Nefroz Modeli Sıçan Glomerüllerinde TGF-b1 Ekspresyonu ve Mezangiyal Değişiklikler. Cerrahpaşa Tıp Dergisi. 2019;43(1):6-12.