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Protective effects of renal fibrosis by renal-specific chitobionic acid- conjugated polysorbitol gene transporter carrying hepatocyte growth factor

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Authors
김상화
Advisor
강경선
Major
의과대학 협동과정 종양생물학전공
Issue Date
2017-08
Publisher
서울대학교 대학원
Keywords
Chitonic-acidHGFGene therapykidney fibrosis
Description
학위논문 (박사)-- 서울대학교 대학원 의과대학 협동과정 종양생물학전공, 2017. 8. 강경선.
Abstract
Chronic kidney disease (CKD) refers to kidney disease that results in structural or functional damage to the kidneys due to a variety of causes, resulting in irreversible loss of nephron and renal function. The incidence and mortality rate of CKD is increasing worldwide, due to the absence of treatment methods and the existence of various causes of disease. Renal fibrosis is a chronic and progressive kidney disorder that is associated with many kidney diseases. Recovery from acute kidney injury involves the regeneration of the tissue, in which the damaged tissue is replaced by new cells of the same lineage. Abnormal or incomplete recovery lead to renal fibrosis, which is a cause of chronic, progressive renal failure. Considerable research has focused on the development of efficient and specific methods to treat renal diseases. Gene therapy using gene carriers has the advantages of high transfer efficiency, low toxicity, and application to various diseases. In addition, non-viral gene carriers also have potential for gene therapy, due to their ease of modification and biocompatibility. This study was demonstrated that the protective effects of kidney – specific chitonic acid-conjugated polysorbitol gene transporter (CBA-PSGT) carrying the gene for hepatocyte growth factor (HGF) as an anti fibrotic factor, against renal fibrosis progression.
First, CBA, a kidney specific ligand, was synthesized, and conjugated it to a PSGT carrier. CBA can effectively target vimentin to the kidney. Vimentin is an intermediate filament protein that is found in vascular endothelial cells, vascular smooth muscle cells and fibroblasts. Therefore, vimentin, which is expressed on the surface of kidney cells or kidney tissues, can be used as a target for gene delivery. Moreover, vimentin is expressed in the renal interstitial region, as well as in normal and abnormal renal tissues. In particular, vimentin can be considered as a marker of renal tubular disorder, owing to its high expression in those disorders, including renal atrophy, inflammation, and fibrosis. The kidney-specific gene transporter CBA-PSGT as a gene carrier was synthesized and evaluated. CBA-PSGT was confirmed a successful gene transporter with high stability, due to DNA complexation, minimal toxicity, and high gene expression efficiency with the gene. In addition, CBA-PSGT was effectively protected from digestion by DNase.
Second, unilateral ureteral obstruction (UUO) animal models were constructed for the evaluation of the protective effects of CBA-PSGT/HGF against renal fibrosis. In the UUO model, the expression of HGF was increased by treatment with CBA-PSGT/HGF. The UUO model causes renal tissue damage, mainly resulting in atrophy of the interstitial tissue of the tubule and fibrosis. In addition, infiltration of inflammatory cells into the tubulointerstitial tissue causes inflammatory cytokine release in the UUO model. The CBA-PSGT/HGF delivery group was detected less damage to the kidney tissue by histological analysis. BUN and creatinine levels were used as kidney damage markers, and the expression levels of inflammatory cytokines, interleukin-6 (IL-6) and IL-1β were deceased in the group that treated of CBA-PSGT/HGF. Renal fibrosis lead to the formation and accumulation of collagen in the renal tissues. Therefore, collagen formation and accumulation were reduced by gene therapy by histological analysis and assessment of the levels of collagen. In addition, the expression level of collagen-related proteins, such as ICAM-1, TIMP-1 and α-SMA, which highly expressed in the setting of renal injury, as well as metalloproteinase (MMPs), which are enzymes that inhibits the formation of extraellular matrix (ECM), were decreased in the CBA-PSGT/HGF complex group.
In summary, a CBA-conjugated gene transporter was successfully synthesized as kidney specific ligand, which targets the vimentin that is highly expressed in the setting of renal disease and damage. It is characterized that the kidney-specific gene transporter. CBA-PSGT was stable due to DNA complexation and it was protected from degradation by DNase
the construct also had low toxicity and high delivery efficiency. In addition, The study was demonstrated that CBA-PSGT carrying HGF, an anti-fibrotic factor, protected against the progression of renal fibrosis in a UUO model. CBA-PSGT should be further investigated, to explore its potential to alleviate UUO and kidney-related disease using high affinity kidney targeting.
Language
English
URI
https://hdl.handle.net/10371/137100
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College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Theses (Ph.D. / Sc.D._협동과정-종양생물학전공)
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