B Cells Limit Repair after Ischemic Acute Kidney Injury

Jang, Hye Ryoun,Gandolfo, Maria Teresa,Ko, Gang Jee,Satpute, Shailesh R.,Racusen, Lorraine,Rabb, Hamid American Society of Nephrology 2010 Journal of the American Society of Nephrology Vol.21 No.4

Aging has small effects on initial ischemic acute kidney injury development despite changing intrarenal immunologic micromilieu in mice

Jang, Hye Ryoun,Park, Ji Hyeon,Kwon, Ghee Young,Park, Jae Berm,Lee, Jung Eun,Kim, Dae Joong,Kim, Yoon-Goo,Kim, Sung Joo,Oh, Ha Young,Huh, Wooseong American Physiological Society 2016 American Journal of Physiology Vol.310 No.4

<P>Inflammatory process mediated by innate and adaptive immune systems is a major pathogenic mechanism of renal ischemia-reperfusion injury (IRI). There are concerns that organ recipients may be at increased risk of developing IRI after receiving kidneys from elder donors. To reveal the effects of aging on the development of renal IRI, we compared the immunologic micromilieu of normal and postischemic kidneys from mice of three different ages (9 wk, 6 mo, and 12 mo). There was a higher number of total T cells, especially effector memory CD4/CD8 T cells, and regulatory T cells in the normal kidneys of old mice. On day 2 after IRI, the proportion of necrotic tubules and renal functional changes were comparable between groups although old mice had a higher proportion of damaged tubule compared with young mice. More T cells, but less B cells, trafficked into the postischemic kidneys of old mice. The infiltration of NK T cells was similar across the groups. Macrophages and neutrophils were comparable between groups in both normal kidneys and postischemic kidneys. The intrarenal expressions of TNF-alpha and VEGF were decreased in normal and postischemic kidneys of aged mice. These mixed effects of aging on lymphocytes and cytokines/chemokines were not different between the two groups of old mice. Our study demonstrates that aging alters the intrarenal micromilieu but has small effects on the development of initial renal injury after IRI. Further study investigating aging-dependent differences in the repair process of renal IRI may be required.</P>

Urinary Angiotensinogen Excretion and Intrarenal Angiotensinogen Expression in Minimal Change Disease Patients

( Hye Ryoun Jang ),( Ajin Jo ),( Ji Hyeon Park ),( Jung Eun Lee ),( Woo Seong Huh ),( Dae Joong Kim ),( Ha Young Oh ),( Yoon Goo Kim ) 대한신장학회 2011 Kidney Research and Clinical Practice Vol.30 No.6

Purpose: Urinary angiotensinogen (AGT) has been reported as an important marker reflecting the activity of intrarenal renin-angiotensin system (RAS) in chronic glomerulonephritis patients. We investigated urinary AGT excretion and intrarenal AGT expression in patients with minimal change disease (MCD). Methods: In 20 patients with biopsy-proven MCD, urinary and plasma AGT was measured using a sandwich ELISA and intrarenal AGT expression was measured with immunohistochemistry. Urine samples from normal healthy volunteers and patients with biopsy-proven thin basement membrane disease (TBM) were used as control groups. Results: MCD patients showed a wide range of natural logarithm of the urinary AGT/creatinine [ln (urinary AGT/Cr)] and the ln (urinary AGT/Cr) was higher in MCD patients compared with normal controls and TBM controls (normal control vs. TBM vs. MCD, 1.2±0.25 vs. 0.9±0.34 vs. 3.2±0.40). Intrarenal AGT expression was diverse in MCD patients (intrarenal AGT, arbitrary unit, 27.39-78.52 in TBM, 0.00-145.80 in MCD). Ln (urinary AGT/Cr) did not show a direct correlation with intrarenal AGT expression, plasma AGT, or urinary protein/creatinine ratio. Conclusion: Urinary AGT excretion and intrarenal AGT expression are enhanced in some MCD patients, suggesting that intrarenal RAS is activated in these patients.

Gitelman 증후군 환자에서 면역조직화학법으로 확인한 원위세관 sodium-chloride cotransporter (NCCT)의 결손

장혜련 ( Hye Ryoun Jang ),허남주 ( Nam Ju Heo ),손민정 ( Min Jung Son ),이재욱 ( Jay Wook Lee ),이정환 ( Jeong Hwan Lee ),전은실 ( Un Sil Jeon ),신성준 ( Sung Jun Shin ),나기영 ( Ki Young Na ),주권욱 ( Kwon Wook Joo ),이정상 ( Jun 대한내과학회 2005 대한내과학회지 Vol.69 No.6

목적 : Gitelman 증후군은 저포타시움혈증, 대사성 알칼리증, 고레닌혈증, 고알도스테론혈증, 요 중 칼슘 배설의 저하 및 저마그네슘혈증을 특징으로 하는 유전성 질환이다. 이는 원위세관 sodium-chloride cotransporter (NCCT)의 유전자 돌연변이에 의하여 발생하는 것으로 알려져 있으나 사람의 신조직에서 NCCT 결손이 증명된 바는 없었다. 방법 : 저자들은 임상적으로 Gitelman 증후군이 의심되는 환자에서 이뇨제를 이용한 신청소율 검사와 유전자 검사를 시행하였고, 이를 통하여 감별진단한 Gitelman 증후군 환자의 신조직에서 인간 NCCT에 대한 토끼 다클론 항체를 이용한 면역조직화학법을 시행하였다. 신세포암으로 신적출술을 시행 받은 환자의 정상 신조직과 전해질 이상이 없었던 사구체신염 환자의 신조직을 각각 정상 대조군과 질환 대조군으로 하였다. 결과 : 대상 환자는 저포타시움혈증과 대사성 알칼리증, 저마그네슘혈증 및 요 중 칼슘 배설의 저하를 보였다. Bartter 증후군과 감별을 위하여 furosemide 및 hydrochlorothiazide를 이용한 신청소율 검사를 시행하였다. 수분 부하를 시행한 기저치(86.1%)에 비해서 furosemide를 투여한 후 distal fractional chloride reabsorption이 감소하였으나(9.7%) hydrochlorothiazide 투여 후에는 변화가 없었다(81.4%). 유전자 검사 결과 SLC12A3 유전자의 돌연변이(S967F)가 발견되었다. 신조직에서 면역조직화학법을 시행한 결과 정상 및 질환 대조군에서는 원위세관 세포의 내강 막 쪽에 NCCT가 뚜렷이 염색되었으나, Gitelman 증후군에서는 원위세관 세포의 NCCT에 대한 면역 반응성이 관찰되지 않았다. 반면에 Na/K-ATPase, Na-K-2Cl cotransporter, calbindin-D28K는 대조군과 대상 환자의 신조직에서 모두 관찰되었다. 결론 : 기능적 검사로 진단된 Gitelman 증후군 환자의 신조직에서 NCCT의 결함을 면역조직화학법으로 확인하였다. Background : Gitelman`s syndrome is an autosomal recessive renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. It is known to be caused by a mutation of SLC12A3 gene coding the sodium-chloride cotransporter (NCCT) in the distal tubule. The defect of NCCT in human renal tissues has not been investigated, and we tested whether the defect of NCCT can be detected in renal tissue of a patient with Gitelman`s syndrome by using immunohistochemistry. Methods : In an adult patient with Gitelman`s syndrome, blood and urine samples were collected for measurement of biochemical parameters. Renal clearance study and gene analysis were performed. Immunohistochemistry was performed on the renal tissue of the patient using a rabbit polyclonal antibody directed against a synthetic peptide corresponding to a portion in the amino terminal tail for human NCCT. Normal human renal tissues from surgical nephrectomy due to renal cell carcinoma and renal biopsy tissues from patients with glomerulonephritis but without any electrolyte disturbance were used as controls. Results : The patient had hypokalemic metabolic alkalosis, hypocalciuria and hypomagnesemia. Renal clearance study revealed a decrease in distal fractional chloride reabsorption after the administration of furosemide. SLC12A3 gene mutation (S967F) was found by direct sequencing method. Immunohistochemistry showed the absence of NCCT staining in the renal tissue of the patient. On the other hand, the immunostaining of other transporters was all positive in renal tissues from both Gitelman`s syndrome patients and controls. Conclusions : We report the absence of intact NCCT in the renal tissue of a Gitelman`s syndrome patient.(Korean J Med 69:642-650, 2005)

Role of T cells in ischemic acute kidney injury and repair

이경호,Hye Ryoun Jang 대한내과학회 2022 The Korean Journal of Internal Medicine Vol.37 No.3

Ischemic acute kidney injury (AKI) is a common medical problem with significant mortality and morbidity, affecting a large number of patients globally. Ischemic AKI is associated with intrarenal inflammation as well as systemic inflammation; thus, the innate and adaptive immune systems are implicated in the pathogenesis of ischemic AKI. Among various intrarenal immune cells, T cells play major roles in the injury process and in the repair mechanism affecting AKI to chronic kidney disease transition. Importantly, T cells also participate in distant organ crosstalk during AKI, which affects the overall outcomes. Therefore, targeting T cell-mediated pathways and T cell-based therapies have therapeutic promise for ischemic AKI. Here, we review the major populations of kidney T cells and their roles in ischemic AKI.

Electronic alerts based on clinical decision support system for post-contrast acute kidney injury

( Hojin Jeon ),( Hye Ryoun Jang ) 대한신장학회 2023 Kidney Research and Clinical Practice Vol.42 No.5

Graves’ Disease and the Risk of End-Stage Renal Disease: A Korean Population-Based Study

조윤영,김봉성,신동욱,Hye Ryoun Jang,김보연,정찬희,김재현,김선욱,정재훈,한경도,김태혁 대한내분비학회 2022 Endocrinology and metabolism Vol.37 No.2

Background: Hyperthyroidism is associated with an increased glomerular filtration rate (GFR) in the hyperdynamic state, which isreversible after restoring euthyroidism. However, long-term follow-up of renal dysfunction in patients with hyperthyroidism has notbeen performed. Methods: This was a retrospective cohort study using the Korean National Health Insurance database and biannual health checkupdata. We included 41,778 Graves’ disease (GD) patients and 41,778 healthy controls, matched by age and sex. The incidences ofend-stage renal disease (ESRD) were calculated in GD patients and controls. The cumulative dose and duration of antithyroid drugs(ATDs) were calculated for each patient and categorized into the highest, middle, and lowest tertiles. Results: Among 41,778 GD patients, 55 ESRD cases occurred during 268,552 person-years of follow-up. Relative to the controls,regardless of smoking, drinking, or comorbidities, including chronic kidney disease, GD patients had a 47% lower risk of developingESRD (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.37 to 0.76). In particular, GD patients with a higher baseline GFR(≥90 mL/min/1.73 m2; HR, 0.33; 95% CI, 0.11 to 0.99), longer treatment duration (>33 months; HR, 0.31; 95% CI, 0.17 to 0.58) orhigher cumulative dose (>16,463 mg; HR, 0.29; 95% CI, 0.15 to 0.57) of ATDs had a significantly reduced risk of ESRD. Conclusion: This was the first epidemiological study on the effect of GD on ESRD, and we demonstrated that GD population had areduced risk for developing ESRD.

Induction of Apoptosis by Vitamin E Succinate in Human Erythroleukemia K562 Cells

장창덕,김종명,안원근,박혜련,Jang, Chang-Deug,Kim, Jong-Myoung,An, Won-Geun,Park, Hye-Ryoun Korean Society of Life Science 2007 생명과학회지 Vol.17 No.7

비타민 E 유도체인 $RRR-{\alpha}-tocopheryl$ succinate (vitamin E succinate, VES)는 만성골수성 백혈병 세포인 K562세포에서 apoptosis를 유도하였다. VES의 처리에 의해 apoptosis가 유도되는 과정에서 K562 세포 내의 ROS의 생성이 증가되었으며, ROS와 관련된$NF-{\kappa}B$, COX-2 그리고 $p21^{WAF1/CIP1}$등의 유전자가 활성화되었다. 뿐만 아니라, apoptosis의 과정 중 중요한 역할을 하는 Bax의 발현증가 및 손상된 DNA의 회복에 중심적 기능을 하는 PARP의 분열이 야기되었다. VES를 처리한 세포의 세포주기 분석에서는 apoptotic phase인 sub-Gl phase에서 세포사멸이 증가되고, 형태적으로는 염색질의 응축이 일어나는 결과로 미루어볼 때 VES는 K562세포의 apoptosis를 유도한 것을 알 수 있다. C57BL/C의 림프종 이종이식을 통한 VES의 항암활성 실험 결과, C57BL/C의 대조군에 비하여 종양의 성장억제를 확인하였으며 높은 생존율을 확인하였다. 이러한 결과는 백혈병 치료에 대한 분자적 기초를 제공하였으며 동물실험을 통하여 보다 실질적인 백혈병 치료의 가능성을 보여주었다. Regulation mechanism of apoptosis has been known to be important for understanding the pathogenesis of a number of human diseases including cancers. The effects of $RRR-{\alpha}-tocopheryl$ succinate(vitamin E succinate, VES) on the cell viability, generation of ROS, expression of proteins involved in apoptosis, and growth of human chronic myelogenous leukemia K562 cells were analyzed in this study. VES treatment not only induced the generation of the ROS but also increased the levels of $NF-{\kappa}B$, COX-2, and $p21^{WAF1/CIP1}$ in K562 cells. It modulates the levels of pro-apoptotic proteins such as Bax provoking the apoptosis in K562 cells. The cleavage of PARP into 89 kDa was also increased upon VES treatment in a dosage-dependent manner. Induction of an apoptosis was evident by the increase of sub-Gl peak and cell shrinkage condensed chromatin in K562 cells treated with VES. It also resulted in an inhibition of tumor growth by 50% and prolonged survival of the Iymphoma-induced mice. This potentiation of VES obtained in vitro and in vivo may indicate the feasibility of more effective chemotherapy in chronic myelogenous leukemia.

Newly Developed Weakness of Lower Extremities Despite Improved Brain Metastasis of Lung Cancer after Radiotherapy

Yang, Jae Hyun,Jang, Young Joo,Ahn, Se Jin,Kim, Hye-Ryoun,Kim, Cheol Hyeon,Koh, Jae Soo,Choe, Du Hwan,Lee, Jae Cheol The Korean Academy of Tuberculosis and Respiratory 2009 Tuberculosis and Respiratory Diseases Vol.67 No.6

An intramedullary spinal cord metastasis (ISCM) rarely develops in systemic cancer but is indicative of a poor prognosis. A 56-year-old man was admitted due to weakness of the lower extremities. He had received radiotherapy 3 months prior for a brain metastasis that had developed 1 year after achieving a complete response from chemotherapy for extended stage small cell lung cancer. Although the brain lesion had improved partially, ISCM from the cervical to lumbar-sacral spinal cords, which was accompanied by a leptomeningeal dissemination, was diagnosed based on magnetic resonance imaging of the spine and cerebrospinal fluid cytology. Finally, he died of sudden cardiac arrest during treatment. This is the first case of ISCM involving the whole spinal segments. Physicians should be aware of the subsequent development of ISCM in lung cancer patients with a previously known brain metastasis who present with new neurological symptoms.

Early, but not late, treatment with human umbilical cord blood-derived mesenchymal stem cells attenuates cisplatin nephrotoxicity through immunomodulation

Park, Ji Hyeon,Jang, Hye Ryoun,Kim, Do Hee,Kwon, Ghee Young,Lee, Jung Eun,Huh, Wooseong,Choi, Soo Jin,Oh, Wonil,Oh, Ha Young,Kim, Yoon-Goo American Physiological Society 2017 American Journal of Physiology Vol.313 No.4

<P>Preemptive treatment with mesenchymal stem cells (MSCs) can attenuate cisplatin-induced acute kidney injury (AKI). However, it is uncertain whether MSC treatment after the development of renal dysfunction prevents AKI progression or if MSC immunomodulatory properties contribute to MSC therapy. In this study, human umbilical cord blood (hUGB)-derived MSCs were used to compare the effects and mechanisms of early and late MSC therapy in a murine model. After cisplatin injection into C57BL/6 mice, hUCB-MSCs were administered on day 1 (early treatment) or day 3 (late treatment). With early treatment, cisplatin nephrotoxicity was attenuated as evidenced by decreased blood urea nitrogen (BUN) and reduced apoptosis and tubular injury scores on day 3. Early treatment resulted in downregulation of intrarenal monocyte chemotactic protein-1. and IL-6 expression and upregulation of IL-10 and VEGF expression. Flow cytometric analysis showed similar populations of infiltrated immune cells in both groups; however, regulatory T-cell (Treg) infiltration was 2.5-fold higher in the early treatment group. The role of Tregs was confirmed by the blunted effect of early treatment on renal injury after Treg depletion. In contrast, late treatment (at a time when BUN levels were 2 -fold higher than baseline levels) showed no renoprotective effects on day 6. Neither the populations of intrarenal infiltrating immune cells (including Tregs) nor cytokine expression levels were affected by late treatment. Our results suggest that early MSC treatment attenuates renal injury by Treg induction and immunomodulation, whereas a late treatment (i.e., after the development of renal dysfunction) does not prevent AK.I. progression or alter the intrarenal inflammatory- micromilieu.</P>