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系統識別號 U0026-0509201308332700
論文名稱(中文) Streptozotocin誘發之糖尿病鼠的腎臟其Klotho和FGF接受器的調節
論文名稱(英文) Regulation of Klotho and FGF receptors (FGFRs) in the kidney of streptozotocin-induced diabetic rats
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 程盟夫
研究生(英文) Meng-Fu Cheng
學號 s98941092
學位類別 博士
語文別 英文
論文頁數 106頁
口試委員 指導教授-鄭瑞棠
指導教授-王明誠
召集委員-方德昭
口試委員-吳昭良
口試委員-許朝添
口試委員-蔡曜聲
中文關鍵字 Klotho  纖維母細胞生長因子接受器(FGFRs)  纖維母細胞生長因子23(FGF23)  氧化壓力  糖尿病腎病變  腎臟纖維化  紅血球生成素接受器(EPOR)  STAT3  慢性腎臟病 
英文關鍵字 Klotho  FGF Receptors (FGFRs)  FGF23  oxidative stress  diabetic nephropathy  renal fibrosis  erythropoietin receptor (EPOR)  STAT3  chronic kidney disease (CKD) 
學科別分類
中文摘要 纖維母細胞生長因子23 (FGF23)-Klotho軸,在腎臟調節磷酸鹽的平衡上,扮演著重要的角色。由骨頭產生的 FGF23可以抑制 NaPi-2a/2ccotransporters的表現和活性維生素D在腎臟的合成。許多研究顯示,FGF23要有功能須先激活FGF接受器(FGFRs),而此接受器需要Klotho作為輔助因子,如此才能進行下游的信號。klotho基因只在部分的組織表現,特別是在腎臟遠曲小管和大腦中的脈絡叢。以前的研究顯示,Klotho似乎與增加對氧化壓力的抗性有關。然而,因高糖值而誘發的氧化壓力所造成的FGF23-Klotho軸的改變仍然不明。在此,我們已對streptozotocin誘發具糖尿病腎病變的糖尿病鼠(STZ rats)使用insulin、phloridzin或抗氧化劑tiron來治療;初步結果顯示:insulin及phloridzin可經由矯正高血糖而逆轉糖尿病大白鼠 (STZ rats) 其在腎臟表現都降低的Klotho和FGFRs;而且,變差的腎功能和腎臟纖維化也都獲得改善;此外,亦發現在不用矯正高血糖之下,使用tiron就可收到上升Klotho和FGFRs的效果,此應與tiron降低了高血糖引起的氧化壓力有關。這個觀點,後來也在體外的MDCK細胞株的高糖暴露實驗中,得到證實。因此,我們認為降低氧化壓力不只能改善腎功能,也復原了在STZ rats 腎臟表現下降的Klotho和FGFRs,以及相對應的腎臟纖維化。
在第四章,經由STZ rats和MDCK腎臟上皮細胞的研究,我們發現高糖值可誘發EPOR的增加,而且是經由STAT3的增加而來。這似乎意味著EPO的治療對高血糖腎臟病可能會有較好的腎臟保護效果。
英文摘要 The fibroblast growth factor23 (FGF23)-Klotho axis plays an important role in renal regulation of phosphate homeostasis. FGF23 produced by bone can suppress the expression of NaPi-2a/2ccotransporters and the synthesis of active vitamin D in the kidney. Many studies suggested that most of the FGF23 functions be conducted through the activation of FGF receptors (FGFRs) needing Klotho as a cofactor to generate the downstream signaling events. The klotho gene is expressed in limited tissues, most notably in distal convoluted tubules in the kidney and choroid plexus in the brain. Previous study suggested that Klotho seems related to increase the resistance of oxidative stress. However, changes of FGF23-Klotho axis in high glucose induced oxidative stress remain unclear. We had used streptozotocin-induced diabetic rats (STZ rats) showing diabetic nephropathy to treat them with insulin, phloridzin or antioxidant tiron. The results showed both insulin and phloridzin reversed the lower Klotho and FGFRs expressions in kidneys of STZ rats through the correction of hyperglycemia. Also, renal functions and renal fibrosis were improved by these treatments. Otherwise, in addition to the improvement of renal functions, the decrease of Klotho and FGFRs expressions in kidney of STZ rats was also reversed by tiron without changing of blood glucose levels. The reduction of oxidative stress induced by high glucose can be considered for this action of tiron. This view was further confirmed in vitro using the high glucose exposed tubular cells. Thus, we considered that decrease of oxidative stress is not only responsible for the improvement of renal function but also for the recovery of Klotho and FGFRs expression, as well as related renal fibrosis in kidney of STZ rats.
Additionally, we also found increased expression of erythropoietin receptor (EPOR) in STZ rats and MDCK cells exposed to high glucose. Both insulin and phloridzin could reduce EPOR expression in kidney of STZ rats after the correction of hyperglycemia. The elevated EPOR expression showed a higher expression of STAT3. A STAT3-specific inhibitor (stattic) reversed the hyperglycemia-induced EPOR expression, both in vitro and in vivo. Hence, the expression of EPOR in kidney was up-regulated by hyperglycemia through a higher expression of STAT3.
論文目次 中文摘要 ..... II
Abstract ..... III
Acknowledgements ..... XI
Abbreviations ..... XII
Chapter 1 ..... 1
Introduction ..... 1
1.1 Diabetic nephropathy in CKD ..... 2
1.2 Hyperphosphatemia in CKD ..... 3
1.3 Phosphate Homeostasis and the FGF23-FGFRs-klotho axis ..... 4
1.4 ROS and FGF23-Klotho Axis in Diabetic Nephropathy ..... 7
1.5 Anemia and CKD ..... 8
1.5.1 EPO and renoprotection ..... 9
1.5.2 Extra-erythropoietic EPOR is functional ..... 11
1.5.3 EPOR responsiveness in hematopoietic and non-hematopoietic tissues ..... 11
1.6 Thesis Aims ..... 12
Chapter 2 ..... 14
Decrease of Klotho in the Kidney of Streptozotocin-induced Diabetic Rats ..... 14
2.1 Background and Aims ..... 14
2.2. Materials and Methods ..... 16
2.2.1 Animal model ..... 16
2.2.2 Western blot analysis ..... 17
2.2.3 Histological analysis ..... 18
2.2.4 Measurement of ROS generation ..... 18
2.2.5 Cell cultures ..... 18
2.2.6 Intracellular ROS detection ..... 19
2.2.7 Statistical analysis ..... 19
2.3 Results ..... 20
2.3.1 Effect of insulin or phloridzin on rats with diabetic nephropathy ..... 20
2.3.2 Effect of antioxidant on rats with diabetic nephropathy ..... 20
2.3.3 Recovery of renal Klotho due to decreased levels of ROS ..... 21
2.3.4 Decrease of Klotho expression levels by glucose in tubular cells ..... 21
2.3.5 Decrease of Klotho expression level in MDCK cells by ROS from high glucose ..... 22
2.4 Discussion ..... 23
2.5 Conclusions ..... 25
2.6 Tables ..... 26
2.7 Figures ..... 28
Chapter 3 ..... 33
Decrease of FGF Receptor (FGFR) and Interstitial Fibrosis in the Kidney of Streptozotocin-induced Diabetic Rats ..... 33
3.1 Background and Aims ..... 33
3.2 Materials and Methods ..... 35
3.2.1 Animal model ..... 35
3.2.2 Histological analysis ..... 36
3.2.3 Immunohistochemical stains ..... 36
3.2.4 Western blotting analysis ..... 37
3.2.5 Cell cultures ..... 37
3.2.6 Measurement of ROS generation ..... 38
3.2.7 Transfection of klotho small interfering RNA (siRNA) and treatment of recombinant Kloth in MDCK cells ..... 38
3.2.8 Statistical analysis ..... 39
3.3 Results ..... 40
3.3.1 Tubulointerstitial fibrosis and decreased FGFR1 level in diabetic rats showing nephropathy ..... 40
3.3.2 Recovery of renal FGFR1 by correction of hyperglycemia ..... 40
3.3.3 Decrease of FGFR1 expression by glucose in tubular cells ..... 41
3.3.4 Decrease of FGFR1 expression in MDCK cells by superoxide from high glucose ..... 41
3.3.5 Decrease of Klotho failed to affect the expression of FGFR1 ..... 42
3.3.6 Effect of tiron on rats with diabetic nephropathy ..... 42
3.4 Discussion ..... 43
3.5 Conclusions ..... 46
3.6 Tables ..... 47
3.7 Figures ..... 49
Chapter 4 ..... 56
Increase of Erythropoietin Receptor (EPOR) in the Kidney of Type 1-like Diabetic Rats ..... 56
4.1 Background and Aims ..... 56
4.2 Materials and Methods ..... 58
4.2.1 Materials ..... 58
4.2.2 Animals ..... 58
4.2.3 Streptozotocin (STZ) induced type 1-like diabetic rats ..... 59
4.2.4 Drug treatments and the sample collections from animals ..... 59
4.2.5 Histological analysis ..... 60
4.2.6 Immunohistochemical stains ..... 60
4.2.7 Cell cultures ..... 61
4.2.8 Western blotting analysis ..... 61
4.2.9 Statistical analysis ..... 62
4.3 Results ..... 63
4.3.1 Increased EPOR level in diabetic rats showing nephropathy ..... 63
4.3.2 Increase in renal EPOR expression reversed by correcting hyperglycemia ..... 63
4.3.3 Increase of EPOR expression by high glucose in tubular cells ..... 64
4.3.4 Increase in STAT3 expression by high glucose in tubular cells ..... 64
4.3.5 The effect of STAT3 specific inhibitor (stattic) on the expression of EPOR ..... 65
4.3.6 Effect of stattic on the expression of EPOR in the kidney of STZ rats ..... 65
4.4 Discussion ..... 66
4.5 Conclusions ..... 68
4.6 Tables ..... 69
4.7 Figures ..... 71
Chapter 5 ..... 77
General Discussion, Conclusion and Prospects ..... 77
5.1 Experimental & Clinical Studies ..... 77
5.1.1 Klotho expression under high glucose condition, in vivo and in vitro ..... 78
5.1.2 FGFR1 expression under high glucose condition, in vivo and in vitro ..... 78
5.1.3 EPOR expression under high glucose condition, in vivo and in vitro ..... 79
5.2 Novelty of my studies ..... 80
5.3 Prospects ..... 81
Bibliography ..... 85
Publication list ..... 103
Thesis-related publications: ..... 103
Publications during PhD study: ..... 103
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