Significance of Intratumoral Fibrosis in Clear Cell Renal Cell Carcinoma

정재원,오훈규,이선재,김영아,정현진 대한병리학회 2018 Journal of Pathology and Translational Medicine Vol.52 No.5

Background: Intratumoral fibrosis (ITF) is a frequent histologic finding in solid organ tumors. Renal cell carcinoma (RCC) is a highly vascularized tumor with different shapes and degrees of ITF and inflammation. ITF is a poor prognostic factor, especially in breast cancer, and is related to intratumoral necrosis (ITN) and intratumoral inflammation (ITI). However, the significance of ITF in RCC has not been fully studied. In this study, we evaluate the relationships between ITF and other clinicopathologic parameters associated with RCC prognosis. Methods: ITF was evaluated in 204 clear cell renal cell carcinoma (CCRCC) specimens according to presence and grade of fibrosis, degree of ITI, and presence of ITN. Lysyl oxidase (LOX) expression in tumor cells was also evaluated with clinicopathologic parameters. Results: Among 204 CCRCC cases, 167 (81.7%) showed ITF, 71 (34.8%) showed ITI, 35 (17.2%) showed ITN, and 111 (54.4%) showed LOX expression. ITF correlated with Fuhrman nuclear grade (p = .046), lymphovascular invasion (LVI) (p = .027), and ITN (p = .036). Patients with ITF had a poor five-year overall survival rate (p = .104). Conclusions: ITF is related to other poor prognostic factors in CCRCC, such as Fuhrman nuclear grade, ITN, and LVI, but ITF itself had no significant correlation with prognosis of CCRCC.

A Novel Dorsal Slit Approached Non-Ischemic Partial Nephrectomy Method for a Renal Tissue Regeneration in a Mouse Model

전소영,김대환,김정식,김현태,유은상,정재욱,하윤석,송필현,정윤기,한동근,정성광,김범수,권태균 한국조직공학과 재생의학회 2018 조직공학과 재생의학 Vol.15 No.4

BACKGROUND: Kidney ischemia–reperfusion (IR) via laparotomy is a conventional method for kidney surgery in a mouse model. However, IR, an invasive procedure, can cause serious acute and chronic complications through apoptotic and inflammatory pathways. To avoid these adverse responses, a Non-IR and dorsal slit approach was designed for kidney surgery. METHODS: Animals were divided into three groups, 1) sham-operated control; 2) IR, Kidney IR via laparotomy; and 3) Non-IR, Non-IR and dorsal slit. The effects of Non-IR method on renal surgery outcomes were verified with respect to animal viability, renal function, apoptosis, inflammation, fibrosis, renal regeneration, and systemic response using histology, immunohistochemistry, real-time polymerase chain reaction, serum chemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and Masson’s trichrome staining. RESULTS: The Non-IR group showed 100% viability with mild elevation of serum blood urea nitrogen and creatinine values at day 1 after surgery, whereas the IR group showed 20% viability and lethal functional abnormality. Histologically, renal tubule epithelial cell injury was evident on day 1 in the IR group, and cellular apoptosis enhanced TUNEL-positive cell number and Fas/caspase-3 and KIM-1/NGAL expression. Inflammation and fibrosis were high in the IR group, with enhanced CD4/CD8-positive T cell infiltration, inflammatory cytokine secretion, and Masson’s trichrome stain-positive cell numbers. The Non-IR group showed a suitable microenvironment for renal regeneration with enhanced host cell migration, reduced immune cell influx, and increased expression of renal differentiation-related genes and anti-inflammatory cytokines. The local renal IR influenced distal organ apoptosis and inflammation by releasing circulating pro-inflammatory cytokines. CONCLUSION: The Non-IR and dorsal slit method for kidney surgery in a mouse model can be an alternative surgical approach for researchers without adverse reactions such as apoptosis, inflammation, fibrosis, functional impairment, and systemic reactions.

당뇨병성 신병증 모델에서 블랙커런트의 사구체 섬유증 및 신장 기능장애 개선 효과

김혜윰(Hye Yoom Kim) 한국식품과학회 2021 한국식품과학회지 Vol.53 No.5

본 연구를 통하여 블랙커런트 추출물의 섭취가 제 2형 당뇨동물 모델인 db/db 마우스에서 혈당 개선 및 사구체 확장, 신장섬유증, 염증을 억제하여 당뇨병성 신병증을 개선했다는 것을 입증했다. 제 2형 당뇨병 db/db 마우스에서 블랙커런트 추출물의 섭취가 인슐린 저항성 및 신장 기능 장애와 같은 당뇨병 관련 대사 장애를 개선하고, 당뇨병성 신병증에 있어 신장 염증 및 신장섬유증을 현저하게 약화시켰다는 것을 보여주었다. 결론적으로, 이러한 연구 결과는 블랙커런트 추출물이 신장 섬유증, 염증 및 이에 따른 당뇨병성 신병증의 예방에 중요한 역할을 할 수 있다는 증거를 제공한다. 따라서 당뇨병 관련 신기능 장애에 대한 블랙커런트 추출물의 보호 역할은 당뇨병성 신병증 개선 건강성 식품 개발에 대한 새로운 통찰력을 제공 할 수 있다. Diabetic nephropathy is a major and representative complication of type 2 diabetes. Hyperglycemia increases the incidence of diabetic nephropathy, and induces kidney inflammation, thereby causing renal fibrosis, which is an important factor in the pathogenesis of diabetic nephropathy. This study investigated the effects of blackcurrant extract (BLC), which has been implicated in diabetic nephropathy in db/db mice, on glomerular fibrosis and renal dysfunction. The results showed that BLC consumption in type 2 diabetic db/db mice ameliorated diabetes-related metabolic disorders, such as insulin resistance and renal dysfunction, and significantly attenuated renal inflammation and renal fibrosis in diabetic nephropathy. In conclusion, these findings suggest that BLC consumption may help prevent renal fibrosis, inflammation, and consequent diabetic nephropathy.

Ischemic Time Associated with Activation of Rejection-Related Immune Responses

남현숙,최진영,김윤태,권혁무,홍종해,김두,한태욱,문태영,김지희,조병렬,우흥명,강경선 한국임상수의학회 2009 한국임상수의학회지 Vol.26 No.2

Ischemia/reperfusion injury (I/RI) is the major cause of acute renal failure and delayed graft function (DGF) unavoidable in renal transplantation. Enormous studies on ischemia damage playing a role in activating graft rejection factors, such as T cells or macrophages, are being reported. Present study was performed to determine whether ischemia time would play an important role in activating rejection-related factors or not in rat models of I/RI. Male Sprague- Dawley rats were submitted to 30, 45, and 60 minutes of warm renal ischemia with nephrectomy or control animals underwent sham operation (unilateral nephrectomy). Renal function and survival rates were evaluated on day 0, 1, 2, 3, 5 and 7. Immunofluorescence staining of dendritic cells (DCs), natural killer (NK) cells, macrophages, B cells, CD4+ and CD8+ T cells were measured on day 1 and 7 after renal I/RI. Survival rates dropped below 50% after day 3 in 45 minutes ischemia. Histologic analysis of ischemic kidneys revealed a significant loss of tubular architecture and infiltration of inflammatory cells. DCs, NK cells, macrophages, CD4+ and CD8+ T cells were infiltrated from a day after I/RI depending on ischemia time. Antigen presenting cells (DCs, NK cells or macrophages) and even T cells were infiltrated 24 hours post-I/RI, which is at the time of acute tubular necrosis. During the regeneration phase, not only these cells increased but B cells also appeared in more than 45 minutes ischemia. The numbers of the innate and the adaptive immune cells increased depending on ischemia as well as reperfusion time. These changes of infiltrating cells resulting from each I/RI model show that ischemic time plays a role in activating rejection related immune factors and have consequences on progression of renal disease in transplanted and native kidneys.

Renal sodium handling and sodium sensitivity

( Alissa A. Frame ),( Richard D. Wainford ) 대한신장학회 2017 Kidney Research and Clinical Practice Vol.36 No.2

The pathophysiology of hypertension, which affects over 1 billion individuals worldwide, involves the integration of the actions of multiple organ systems, including the kidney. The kidney, which governs sodium excretion via several mechanisms including pressure natriuresis and the actions of renal sodium transporters, is central to long term blood pressure regulation and the salt sensitivity of blood pressure. The impact of renal sodium handling and the salt sensitivity of blood pressure in health and hypertension is a critical public health issue owing to the excess of dietary salt consumed globally and the significant percentage of the global population exhibiting salt sensitivity. This review highlights recent advances that have provided new insight into the renal handling of sodium and the salt sensitivity of blood pressure, with a focus on genetic, inflammatory, dietary, sympathetic nervous system and oxidative stress mechanisms that influence renal sodium excretion. Increased understanding of the multiple integrated mechanisms that regulate the renal handling of sodium and the salt sensitivity of blood pressure has the potential to identify novel therapeutic targets and refine dietary guidelines designed to treat and prevent hypertension.

Identification of apolipoproteinA1 reduction in the polycystic kidney by proteomics analysis of the Mxi1-deficient mouse

Yoo, Kyung Hyun,Kim, Yo Na,Lee, Min Joo,Seong, Je Kyung,Park, Jong Hoon WILEY-VCH Verlag 2009 Proteomics Vol.9 No.15

<P>Autosomal dominant polycystic kidney disease is one of the most common human monogenic diseases in which extensive epithelial-lined cysts develop in kidney and other organs. Affected kidneys are not only characterized by the formation of cysts, but also by changes associated with the extracellular matrix and interstitial inflammation, which can progress to fibrosis and loss of renal function. Mxi1 protein, which is a c-myc antagonist, may be essential in controlling cellular growth and differentiation. Previously, multiple tubular cysts were observed in kidney of Mxi1-deficient mice aged 6 months and more. Presently, 2-DE and MALDI-TOF MS was employed to identify the differentially expressed proteins in the kidney. Several proteins were identified, among them, apolipoproteinA1 which is a major component of the high-density lipoprotein complex and has anti-inflammation effects, was significantly decreased in the Mxi1-deficient mouse. We confirm the development of inflammation and renal fibrosis and the expression of extracellular matrix molecules including transforming growth factor were also increased in cystic kidney. These results indicate that expression of proteins related with inflammation and renal fibrosis changes by Mxi1 inactivation in polycystic kidney.</P>

말기 신부전 환자에서 적극적 투석 요법이 염증 반응을 통해 좌심실 수축기능에 미치는 영향

부창수 ( Chang Su Boo ),우영석 ( Young Seok Woo ),이재원 ( Jae Won Lee ),고강지 ( Gang Jee Ko ),조상경 ( Sang Kyung Jo ),조원용 ( Won Yong Cho ),김형규 ( Hyoung Kyu Kim ) 대한신장학회 2008 Kidney Research and Clinical Practice Vol.27 No.3

목적: 울혈성 심부전은 말기신질환자에 있어 생명을 위협하는 급성 합병증이다. 적극적 투석 요법은 효과적으로 체액량을 감소시키고 요독물질을 제거하여 심장의 수축기 기능을 향상시킨다. 비록 심혈관계 질환의 병인에 염증반응이 중요한 역할을 하나, 적극적 투석 요법이 염증인자들과 좌심실의 수축기 기능장애에 어떠한 영향을 미치는지에 대해서는 명확하지 않다. 이번 연구는 적극적 투석요법이 좌심실의 수축기 기능과 혈청 싸이토카인에 어떠한 변화를 일으키는지 조사하였다. 방법: 투석을 받는 말기신질환자 중에서 좌심실 기능부전으로 인한 급성 폐부종이 발생한 환자를 대상으로 하였다. 적극적 투석요법은 매일 4시간씩 7일간 연속적으로 시행하였다. 모든 결과는 전향적으로 모았으며 적극적 투석요법 전후로 심장초음파 검사를 시행하였다. 혈청 TNF-α 와 IL-10을 적극적 투석요법 전후로 비교하였고 내독소 자극 후 이들 싸이토카인들 역시 비교하였다. 결과: 적극적 투석요법 이후에 환자들의 체중과 평균동맥혈압은 의미 있게 감소하였고 그리고 심박출계수는 적극적 투석 이후 의미 있게 증가하였다. 혈청 IL-10과 TNF-α는 적극적 투석요법 후에 의미 있게 감소하였다. 반면 내독소로 자극 후 분비되는 IL-10과 TNF-α는 의미있게 증가하였다. 또한 CRP 변화 정도와 심박출계수 변화 정도는 의미 있는 상관관계를 보여주었다. 결론: 급성 좌심실 기능부전을 동반한 말기신질환자에서 적극적 투석요법은 심박출계수를 의미 있게 증가시켰으며 적절한 면역반응을 회복시키며 염증반응을 조절하는 것으로 나타났다. 따라서 급성 좌심실 기능부전을 동반한 말기신질환자에 있어 적극적 투석요법을 시행하는 것이 심기능 개선 및 염증반응 조절 및 면역반응의 회복증진에 도움이 될 것으로 생각된다. Purpose: CHF is a life threatening acute complication in ESRD populations. An intensive hemodialysis (HD) has been effective in reducing intravascular volume and in removing uremic toxin with improved systolic function. Although recent progress has identified an inflammation as an important contributor to the pathogenesis of CVD, the effect of intensive HD on inflammatory parameters and left ventricle (LV) systolic dysfunction is not clear. The purpose of this study is to examine the effect of intensive HD on LV systolic function and serum cytokines levels. Methods: Among ESRD patients who underwent dialysis and developed acute pulmonary edema due to LV systolic dysfunction were enrolled. Intensive HD consisted of daily 4 hours HD for 7 consecutive days. Data were prospectively collected and 2-D echocardiography was done before and after intensive HD. Serum levels of TNF-α and IL-10 were compared and lipopolysaccharide (LSP)-stimulated of these cytokines were measured. Results: After intensive HD, weight and mean arterial blood pressure decreased significantly and ejection fraction (EF) increased significantly. Serum IL-10 and TNF-α levels decreased significantly after intensive HD. In contrast, LPS stimulated production of these cytokines increased significantly after intensive HD. The difference of CRP between after HD and before HD was negatively correlated with the difference of EF. Conclusion: In ESRD patients with acute LV dysfunction, intensive HD significantly improved EF and restored the immune responsiveness. These results suggest that intensive HD has the advantage of improving EF through modulating inflammation and correcting immune dysfunction in ESRD patients with acute LV dysfunction.

A Case of Idiopathic Aortitis with Left Renal Vein Thrombosis

Hyeon Jeong Yun,Jin Uk Jeong,Jong Ho Shin,Jin Ho Choi,Young Min Na,Jin Cheol Myeong,Ki Tae Bang 순천향대학교 순천향의학연구소 2014 Journal of Soonchunhyang Medical Science Vol.20 No.2

A 38-year-old man was admitted to the hospital because of abrupt left flank pain. He had no fever and physical examination revealed tenderness of the left costovertebral angle. Laboratory data revealed white blood cell 16,060/μL, C-reactive protein 0.93 mg/ dL. Urinalysis showed more than 1/2 red cells per high-power field with severe proteinuria (4+). Enhanced computed tomography (CT) showed the thickened abdominal aorta wall with partial thrombus. The thickened aorta wall compressed the left renal vein and it caused left renal vein thrombosis. Abdominal CT findings suggested aortitis of the abdominal aorta with complication of left renal vein. We could exclude other types of aortitis including autoimmune aortitis, Takayasu’s arteritis, giant cell arteritis, and infectious causes based on a serologic test and the history of the patient. Therefore, the patient was diagnosed with idiopathic aortitis and treated with glucocorticoid. After treatment, his symptoms disappeared and a follow-up CT showed decreased mural thickening of the abdominal aorta. Isolated idiopathic aortitis presented with renal vein thrombosis is extremely rare and has not been reported in Korea yet. We present a rare case report on idiopathic aortitis of the abdominal aorta with complication of left renal vein thrombosis.

The investigation of macrophage infiltration in the early phase of ischemic acute renal failure in mice

( Soo Jeong Yu ),( Dong Jin Oh ),( Suk Hee Yu ) 대한내과학회 2008 The Korean Journal of Internal Medicine Vol.23 No.2

Background/Aims: Inflammation plays a key role in ischemic acute renal failure (ARF). The present study investigated the infiltration of macrophages in the early phase of ischemic ARF in mice. Methods: Ischemic ARF was induced by renal clamping for 22 min, while the control mice underwent sham surgery (no clamping). The serum creatinine and blood urea nitrogen (BUN) levels were measured in the control and post-ischemia mice. Immunofluorescence staining was used to measure the number of CD 11b-positive cells in the kidney tissue sections to determine the amount of post-ischemic macrophage infiltration. Lipo-Cl2MBP (clodronate) for macrophages depletion was injected via a tail vein 5 d before ischemia induction and again 2 d before ischemia induction. Results: The study found that the post-ischemia mice had higher levels of serum creatinine and BUN at 16 and 24 h compared to the controls. Immunofluorescence staining showed there were more macrophages in the post-ischemic tissue at 2, 8, 16 and 24 h compared to the control tissue, and that most of these macrophages were located in the outer medulla. The mice treated with clodronate prior to ischemia induction were found to have lower levels of serum creatinine compared to those mice that weren`t treated with clodronate. Conclusions: There was significant infiltration of macrophages from the early phase of ischemic ARF, and this peaked at 16-24 h. Macrophage depletion using clodronate was protective against ischemic ARF.

Effect of norgalanthamine on renal injury induced by carbon tetrachloride in mice

Nayeon Yang,Myungsoon Ko,Minhwa Jang,Eunjun Jang,Dowook Yu,Wootaek Hong,Seongbeom Bae,Jieun Ryoo,Taekyun Shin,Meejung Ahn 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7

Norgalanthamine is a major component of Crinum asiaticum var. japonicum that exhibits several biological activities. This study evaluated the anti-inflammatory and anti-oxidative properties of norgalanthamine in mice with carbon tetrachloride (CCl4)-induced renal injury. Norgalanthamine (1 and 10 mg/kg) was orally administered to mice for 7 or 14 days, after which renal injury was induced by CCl4 (1.5 ml/kg, i.p.). The vehicle and positive controls consisted of phosphate-buffered saline and silymarin (100 mg/kg), respectively. In CCl4-injured mice, norgalanthamine pretreatment significantly reversed the increases in serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels, and the decrease in the serum glucose level. The histopathological evaluation and Iba-1 immunoreactivity also supported the protective effects of norgalanthamine against CCl4-induced kidney injury. These results suggest that norgalanthamine ameliorates oxidative renal injury, possibly through reducing enhancing antioxidant enzymes, and suppressing infiltrated macrophages.