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While the relationship between circulating osteoprotegerin (OPG) and cardiovascular events is well-established in the general population, its association with cardiovascular risks in chronic kidney disease (CKD) patients remains less robust. This study hypothesized that elevated circulating OPG levels might be associated with an increased risk of major adverse cardiac events (MACE) in CKD patients, a total of 2,109 patients with CKD stages 1 through pre-dialysis 5 from the KNOW-CKD cohort were categorized into quartiles based on serum OPG levels. The primary outcome of the study was 3-point MACE, defined as a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiac death. The median follow-up duration was 7.9 years. The cumulative incidence of 3-point MACE significantly varied across serum OPG levels in Kaplan-Meier curve analysis (P < 0.001, log-rank test), with the highest incidence observed in the 4th quartile. Cox regression analysis indicated that, relative to the 1st quartile, the risk of 3-point MACE was significantly higher in the 3rd (adjusted hazard ratio 2.901, 95% confidence interval 1.009 to 8.341) and the 4th quartiles (adjusted hazard ratio 4.347, 95% confidence interval 1.410 to 13.395). In conclusion, elevated circulating OPG levels are associated with adverse cardiovascular outcomes in pre-dialysis CKD patients., (© 2024. The Author(s).)

The prevalence of kidney diseases has been increasing worldwide due to the aging population and has results in an increased socioeconomic burden as well as increased morbidity and mortality. A deep understanding of the mechanisms underlying the physiological regulation of the kidney and the pathogenesis of related diseases can help identify potential therapeutic targets. The farnesoid X receptor (FXR, NR1H4) is a primary nuclear bile acid receptor that transcriptionally regulates bile acid homeostasis as well as glucose and lipid metabolism in multiple tissues. The roles of FXR in tissues other than hepatic and intestinal tissues are poorly understood. In studies over the past decade, FXR has been demonstrated to have a protective effect against kidney diseases through its anti-inflammatory and antifibrotic effects; it also plays roles in glucose and lipid metabolism in the kidney. In this review, we discuss the physiological role of FXR in the kidney and its pathophysiological roles in various kidney diseases, including acute kidney injury and chronic kidney diseases, diabetic nephropathy, and kidney fibrosis. Therefore, the regulatory mechanisms involving nuclear receptors, such as FXR, in the physiology and pathophysiology of the kidney and the development of agonists and antagonists for modulating FXR expression and activation should be elucidated to identify therapeutic targets for the treatment of kidney diseases., (© 2023. The Author(s).)

Hypertension is the leading risk factor for end-stage renal disease (ESRD). However, the association between sustained exposure to increased blood pressure (BP) and ESRD is not well established. This study investigated whether the cumulative hypertension burden is a substantial risk factor for ESRD. The incidence of ESRD among 2,144,801 participants identified from the Korean National Health Insurance Service database who had documented BP assessment data in their annual health check-up data from between 2006 and 2010, was determined. Over a median follow-up of 7.2 years, ESRD was identified in 1758 participants. Hypertension burden was defined as the cumulative exposure to hypertension (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) during four consecutive follow-up periods and ranged from 0 to 4. The hypertension burden was as follows: 0 (n = 1,164,488), 77.6%; 1 (n = 292,377), 13.6%; 2 (n = 114,397), 5.3%; 3 (n = 52,671), 2.5%; and 4 (n = 20,886), 1.0%. Compared to the hypertension burden of 0, the adjusted hazard ratio for ESRD was 1.35, 1.54, 1.51, and 2.28 for hypertension burdens of 1, 2, 3, and 4, respectively. A positive dose-dependent relationship between hypertension burden and ESRD was found (P for interaction < 0.001). This association was maintained for sustained exposure to both systolic and diastolic hypertension burden. In conclusion, hypertension burden increases the risk of ESRD. Our study underlines the usefulness of a new assessment of the hypertension burden over a certain period for predicting the risk of ESRD in a large population-based cohort., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Identification of individuals at risk of hypertension development based on socio-economic status have been inconclusive, due to variable definitions of low socio-economic status. We investigated whether educational status of individuals or their parents predicts prevalent hypertension in young adult population, by analyzing data of more than 37,000 non-institutionalized subjects from Korea National Health and Nutrition Examination Survey 2008 to 2017. Although low educational status of individual subjects was robustly associated with elevation of systolic blood pressure and increased prevalence of hypertension in general population, its impact on prevalent hypertension differed across age subgroups, and was remarkably attenuated in young adults. Parental educational status was significantly associated with prevalent hypertension in young adults, but not or only marginally in elderly population. Low parental educational status was also associated with high sodium intake in young adults, irrespective of subject's own educational status. These collectively indicate that parental educational status, rather than individual's own educational status, better and independently predicts prevalent hypertension in young adults, and that young adults with low parental educational status are prone to intake more sodium, possibly contributing to the increased risk of hypertension development. We expect that our findings could help define young individuals at risk of high sodium intake and hypertension.

High serum adiponectin is noted in several conditions of chronic kidney disease (CKD) and is a predictor for end stage renal disease. However, the relationship between adiponectin level and renal disease progression is not well established. This study aimed to determine the relationship between serum adiponectin levels and CKD progression. This prospective longitudinal study included 2238 patients from the Korean Cohort Study for Outcomes in Patients with Chronic Kidney Disease. Patients were divided into quartiles according to their serum adiponectin level. Composite renal outcome was defined as one or more of the following: initiation of dialysis or transplantation, a two-fold increase in baseline serum creatinine levels, or a 50% decline in the estimated glomerular filtration rate (eGFR) during the follow-up period. A cox proportional hazard ratio model was applied to analyze the relationship between composite renal outcome and serum adiponectin levels. Serum adiponectin level was inversely associated with eGFR (p < 0.001) and positively correlated with urine albumin-creatinine ratio. The highest quartile of serum adiponectin was associated with an increased risk of adverse renal outomes (HR, 1.39; 95%CI, 1.05-1.84; p=0.021). On time-dependent receiver operating characteristic curve analysis, predictive ability of adiponectin for renal outcomes disappeared after adjusting for eGFR. Therefore, serum adiponectin may be a biomarker of renal dysfunction rather than a true risk factor in CKD progression.

Angiotensin-[1-7] (Ang-[1-7]) antagonize the actions of the renin-angiotensin-system via the Mas receptor and thereby exert renoprotective effects. Murine recombinant angiotensin-converting enzyme (ACE)2 was reported to show renoprotective effects in an experimental Alport syndrome model; however, the protective effect of direct administration of Ang-[1-7] is unknown. Here, we used Col4a3 -/- mice as a model of Alport syndrome, which were treated with saline or Ang- [1-7]; saline-treated wild-type mice were used as a control group. The mice were continuously infused with saline or Ang-[1-7] (25 μg/kg/h) using osmotic mini-pumps. Col4a3 -/- mice showed increased α-smooth muscle actin (SMA), collagen, and fibronectin expression levels, which were attenuated by Ang-[1-7] treatment. Moreover, Ang-[1-7] alleviated activation of transforming growth factor-β/Smad signaling, and attenuated the protein expression of ED-1 and heme oxygenase-1, indicating reduction of renal inflammation. Ang-[1-7] treatment further reduced the expression levels of inflammatory cytokines and adhesion molecules and attenuated apoptosis in human kidney cells. Finally, Ang-[1-7] downregulated TNF-α converting enzyme and upregulated ACE2 expression. Thus, treatment with Ang-[1-7] altered the ACE2-Ang-[1-7]-Mas receptor axis in the kidneys of Col4a3 -/- mice to attenuate the nephropathy progression of Alport syndrome.

The impact of obesity on health-related quality of life (HRQoL) in chronic kidney disease (CKD) population has not been elucidated, despite the impairment of HRQoL in the obese among general population. We hypothesized that the impact of obesity on HRQoL might be confounded by impaired renal function in CKD population, and that CKD would attenuate the impact of obesity on HRQoL. To compare the impact of obesity on HRQoL according to kidney function, 17,001 subjects from Korea National Health and Nutrition Examination Survey (2008-2011) were categorized by estimated glomerular filtration rate (eGFR), as follows: group 1, eGFR ≥ 90 mL/min/1.73 m 2 ; group 2, eGFR of 60-89 mL/min/1.73 m 2 ; group 3, eGFR < 60 mL/min/1.73 m 2 . The association between obesity parameters (body mass index, waist circumference and, truncal fat mass) and HRQoL parameters (EQ-5D index and EQ-VAS) were cross-sectionally analyzed. Despite robust correlations between obesity parameters and low EQ-5D index or EQ-VAS in general population, no significant association was observed in group 3 population. Impact of obesity on HRQoL in CKD population was only limitedly observed in the mobility domain of EQ-5D, as mobility limitation was associated with increased body mass index or waist circumference regardless of kidney function. Therefore, the impact of obesity on HRQoL seems significantly attenuated in CKD population, suggesting that the risk of obesity should not be over-estimated in patients with CKD, especially with respect to HRQoL.

We analyzed data from the Korean National Health Insurance Service (NHIS) to investigate whether smoking increases the risk of end-stage kidney disease (ESKD). This retrospective nationwide population-based cohort study included the data of 23,232,091 participants who underwent at least one health examination between 2009 and 2012. Smoking status was recorded at baseline. The incidence of ESKD was identified via ICD-10 codes and special medical aid codes from the Korean National Health Insurance Service database till December 2016. A Cox proportional-hazards model with multivariable adjustment was used to evaluate the association between smoking and ESKD incidence. Overall, 24.6% of participants were current smokers; 13.5% and 61.9%, were ex- and non-smokers, respectively. Overall, 45,143 cases of ESKD developed during the follow-up period. Current smokers (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.35-1.43) and ex-smokers (HR, 1.09; 95% CI, 1.06-1.12) demonstrated a significant increase in the adjusted risk of ESKD compared to non-smokers. The risk of ESKD was directly proportional to the smoking duration, number of cigarettes smoked daily, and pack-years. In conclusion, smoking is associated with a greater risk of ESKD in the general Korean population; the risk increases with an increase in the smoking duration, number of cigarettes smoked daily, and pack-years.

The impact of health-related quality of life (HRQOL) on outcomes remains unclear in chronic kidney disease (CKD) patients despite its importance in socioeconomic aspects and individual health. We aim to identify the relationship between HRQOL and progression of CKD in pre-dialysis patients. A total 1622 patients with CKD were analyzed in the KoreaN cohort Study for Outcomes in patients With Chronic Kidney Disease, a prospective cohort study. CKD progression was defined as one or more of the following: initiation of dialysis or transplantation, a two-fold increase in baseline serum creatinine levels, or a 50% decline in the estimated glomerular filtration rate during the follow-up period. The group with CKD progression had lower scores of HRQOL than the group without CKD progression. A fully adjusted Cox proportional hazard ratio model showed that each low baseline physical and mental component summary score was associated with a higher risk of CKD progression. In Kaplan-Meier survival analysis using propensity score matched data, only low physical component summary scores showed statistical significance with CKD progression. Our study highlights low physical component summary score for an important prognostic factor of CKD progression. Risk-modification interventions for high-risk patients may provide benefits to individuals.

Activation of the epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 3 (Stat3) signaling pathway has been reported to be associated with renal fibrosis. We have recently demonstrated that peroxiredoxin V (PrdxV) acted as an antifibrotic effector by inhibiting the activity of Stat3 in TGF-β-treated NRK49F cells. However, the underlying mechanism of PrdxV remains poorly understood. To investigate molecular mechanism of PrdxV, we used a transgenic mouse model expressing PrdxV siRNA (PrdxV si mice) and performed unilateral ureteral obstruction (UUO) for 7 days. 209/MDCT cells were transiently transfected with HA-tagged WT PrdxV and C48S PrdxV. Transgenic PrdxV si mice displayed an exacerbated epithelial-to-mesenchymal transition (EMT) as well as an increase in oxidative stress induced by UUO. In the UUO kidney of the PrdxV si mouse, knockdown of PrdxV increased Tyr1068-specific EGFR and Stat3 phosphorylation, whereas overexpression of WT PrdxV in 209/MDCT cells showed the opposite results. Immunoprecipitation revealed the specific interaction between WT PrdxV and Stat3 in the absence or presence of TGF-β stimulation, whereas no PrdxV-EGFR or C48S PrdxV-Stat3 interactions were detected under any conditions. In conclusion, PrdxV is an antifibrotic effector that sustains renal physiology. Direct interaction between PrdxV and Stat3 through Cys48 is a major molecular mechanism.

The prevalence of hyperuricemia and chronic kidney disease (CKD) has been steadily increasing. The role of hyperuricemia and efficacy of uric acid-lowering agents against CKD progression remain controversial. This study aimed to evaluate the effect of hyperuricemia and uric acid-lowering agents on the progression of CKD. A total 2042 patients with CKD were analyzed in the KoreaN cohort Study for Outcomes in patients With Chronic Kidney Disease (KNOW-CKD), a prospective cohort study. Patients were classified into quartiles on the basis of their serum uric acid level and the prevalence of advanced CKD was higher in patients with a high uric acid level. A composite renal outcome was defined as one or more of the following: initiation of dialysis or transplantation, a two-fold increase in baseline serum creatinine levels, or a 50% decline in the estimated glomerular filtration rate during the follow-up period. A Cox proportional hazard ratio model was applied to analyze the relationship between composite renal outcome and uric acid levels. The risk of progression to renal failure increased by 28% (hazard ratio [HR], 1.277; 95% confidence interval [CI], 1.212-1.345) for each 1 mg/dl increase in the baseline uric acid level. In multivariate models, an association was found between the highest quartile of uric acid and increased risk of composite renal outcome (HR, 3.590; 95% CI, 2.546-5.063). A propensity score matching analysis was performed to survey the effect of uric acid lowering agent. Both allopurinol and febuxostat did not affect the renal outcome. In conclusion, hyperuricemia appears to be an independent risk factor for composite renal outcome, but allopurinol and febuxostat did not show reno-protective effect.

Tubulointerstitial fibrosis is a common feature of kidney disease. Histone deacetylase (HDAC) inhibitors have been reported to attenuate renal fibrosis progression. Here, we investigated the effect of CG200745, a novel HDAC inhibitor, on renal fibrosis development in a mouse model of unilateral ureteral obstruction (UUO). To examine the effects of CG200745 on renal fibrosis in UUO, C57BL/6 J male mice were divided into three groups: control, UUO, and CG200745 (30 mg/kg/day)-treated UUO groups. CG 200745 was administered through drinking water for 1 week. Human proximal tubular epithelial (HK-2) cells were also treated with CG200745 (10 µM) with or without TGF-β (2 ng/mL). Seven days after UUO, plasma creatinine did not differ among the groups. However, plasma neutrophil gelatinase-associated lipocalin (NGAL) levels were markedly increased in the UUO group, which were attenuated by CG200745 treatment. UUO kidneys developed marked fibrosis as indicated by collagen deposition and increased α-smooth muscle actin (SMA) and fibronectin expression. CG200745 treatment attenuated these fibrotic responses and suppressed UUO-induced production of transforming growth factor-beta1 (TGF-β) and phosphorylation of Smad-2/3. CG200745 treatment also attenuated UUO-induced inflammation as indicated by the expression of inflammatory markers. Furthermore, CG200745 attenuated phosphorylation of p38 mitogen-activated protein kinase in UUO kidneys. In HK-2 cells, TGF-β induced the expression of α-SMA and fibronectin, which were attenuated by CG200745 cotreatment. These results demonstrate that CG200745, a novel HDAC inhibitor, has a renoprotective effect by suppressing renal fibrosis and inflammation in a UUO mouse model.

Ischemia/reperfusion injury triggers acute kidney injury (AKI) by aggravating oxidative stress mediated mitochondria dysfunction. The peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a master player that regulates mitochondrial biogenesis and the antioxidant response. We postulated that PGC-1α functions as cytoprotective effector in renal cells and that its regulation mechanism is coordinated by nuclear factor erythroid 2-related factor 2 (Nrf-2). In this study, to understand the effect and molecular mechanisms of PGC-1α, we developed an empty vector or PGC-1α-overexpressing stable cell lines in HK-2 cells (Mock or PGC-1α stable cells). PGC-1α overexpression increased the viability of cells affected by H 2 O 2 mediated injury, protected against H 2 O 2 -mediated apoptotic events and inhibited reactive oxygen species accumulation in the cytosol and mitochondria as compared to that in Mock cells. The cytoprotective effect of PGC-1α was related to Nrf-2 upregulation, which was counteracted by Nrf-2-specific knockdown. Using inhibitor of p38, we found that regulation of the p38/glycogen synthase kinase 3β (GSK3β)/Nrf-2 axis was involved in the protective effects of PGC-1α. Taken together, we suggest that PGC-1α protects human renal tubule cells from H 2 O 2 -mediated apoptotic injury by upregulating Nrf-2 via GSK3β inactivation mediated by activated p38.

Swine influenza A viruses (SwIV) cause significant economic losses in animal husbandry as well as instances of human disease and occasionally give rise to human pandemics, including that caused by the H1N1/2009 virus. The lack of systematic and longitudinal influenza surveillance in pigs has hampered attempts to reconstruct the origins of this pandemic. Most existing swine data were derived from opportunistic samples collected from diseased pigs in disparate geographical regions, not from prospective studies in defined locations, hence the evolutionary and transmission dynamics of SwIV are poorly understood. Here we quantify the epidemiological, genetic and antigenic dynamics of SwIV in Hong Kong using a data set of more than 650 SwIV isolates and more than 800 swine sera from 12 years of systematic surveillance in this region, supplemented with data stretching back 34 years. Intercontinental virus movement has led to reassortment and lineage replacement, creating an antigenically and genetically diverse virus population whose dynamics are quantitatively different from those previously observed for human influenza viruses. Our findings indicate that increased antigenic drift is associated with reassortment events and offer insights into the emergence of influenza viruses with epidemic potential in swine and humans.

This study was designed to evaluate the possible renoprotective effects of rosiglitazone (RGT), a peroxisome proliferator-activated subtype gamma receptor agonist, in deoxycorticosterone acetate (DOCA)-salt hypertension and its role in endogenous endothelin-1 (ET-1) production and renal fibrosis associated with inflammation. Rats were implanted with DOCA strips (200 mg kg(-1)) at 1 week after unilateral nephrectomy. DOCA-salt rats received control diet with or without RGT (10 mg kg(-1) per day). Systolic blood pressure was measured by the tail-cuff method. Glomerulosclerosis and tubulointerstitial fibrosis were evaluated on kidney sections. The expression of ED-1, cyclooxygenase-2 (COX-2), heat shock protein-25 (HSP25) and transforming growth factor-beta1 (TGF-beta1) was determined in the kidney by semiquantitative immunoblotting. In DOCA-salt rats, systolic blood pressure was increased, whereas creatinine clearance decreased compared with controls, which were counteracted by RGT treatment. Tubular injury and glomerulosclerois in the histological study were prominent in DOCA-salt rats, which were counteracted by RGT treatment. ET-1 expression was increased in DOCA-salts rats, which was attenuated by RGT treatment. The expression of TGF-beta1, ED-1 and COX-2 was increased in DOCA-salt, which was attenuated by RGT treatment. In conclusion, RGT treatment decreases blood pressure and is effective in preventing the progression of renal injury in DOCA-salt hypertension, the mechanisms of which are associated with anti-inflammatory and anti-fibrotic effects through reducing the overexpression of ET-1, ED-1, COX-2 and TGF-beta1 in the kidney.

In March and early April 2009, a new swine-origin influenza A (H1N1) virus (S-OIV) emerged in Mexico and the United States. During the first few weeks of surveillance, the virus spread worldwide to 30 countries (as of May 11) by human-to-human transmission, causing the World Health Organization to raise its pandemic alert to level 5 of 6. This virus has the potential to develop into the first influenza pandemic of the twenty-first century. Here we use evolutionary analysis to estimate the timescale of the origins and the early development of the S-OIV epidemic. We show that it was derived from several viruses circulating in swine, and that the initial transmission to humans occurred several months before recognition of the outbreak. A phylogenetic estimate of the gaps in genetic surveillance indicates a long period of unsampled ancestry before the S-OIV outbreak, suggesting that the reassortment of swine lineages may have occurred years before emergence in humans, and that the multiple genetic ancestry of S-OIV is not indicative of an artificial origin. Furthermore, the unsampled history of the epidemic means that the nature and location of the genetically closest swine viruses reveal little about the immediate origin of the epidemic, despite the fact that we included a panel of closely related and previously unpublished swine influenza isolates. Our results highlight the need for systematic surveillance of influenza in swine, and provide evidence that the mixing of new genetic elements in swine can result in the emergence of viruses with pandemic potential in humans.

Eight patients with Philadelphia chromosome-positive (Ph(+)) leukaemia relapsing from stem cell transplantation (SCT) (one syngeneic and seven allogeneic) were treated with the tyrosine kinase inhibitor STI571. Five patients relapsing as chronic myeloid leukaemia (CML) in chronic phase achieved a complete haematological response, with complete and major cytogenetic responses occurring in four and one cases, respectively. One patient became negative for BCR/ABL in the bone marrow. Three patients relapsed as acute leukaemia (two CML in myeloblastic crisis and one Ph(+) acute lymphoblastic leukaemia), all of whom achieved haematological and cytogenetic responses. One patient also became BCR/ABL negative. However, pancytopenia and graft-versus-host disease led to cessation of treatment in the remaining two cases, which was followed by disease recurrence refractory to further STI treatment. Our results showed that Ph(+) leukaemic relapses after SCT might respond well to STI571 therapy.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked hemolytic enzymopathy affecting 3% of Southern Chinese males. Among 275 adult allogeneic hematopoietic stem cell transplantations (SCT), five cases (1.8%) each of donors and recipients were G6PD deficient. Among 107 autologous SCT, four patients (3.7%) were G6PD deficient. All subjects were male, except for two female patients with chronic myeloid leukemia (CML). The incidence of G6PD deficiency in female CML patients was significantly higher than the background female incidence (P = 0.004), but comparable with that in the males (P = 0.664). There was no significant hemolysis or delay in red cell engraftment, and all but one patient converted to donor G6PD screening status. One female patient achieved partial correction of her G6PD status and relapsed at 10 months. We suggest that G6PD deficiency should be tested for in all marrow donors and recipients in susceptible populations. From our data, there is a suggestion of increased clinical incidence of G6PD deficiency in female patients with multi-lineage clonal marrow disorders.

The sympathetic nervous system plays a cardinal role in regulating cardiac function through releasing the neurotransmitter norepinephrine (NE). In comparison with central nervous system, the molecular mechanism of NE uptake in myocardium is not clear. In present study, we proved that in rat the CNS type of NE transporter (NET) was also expressed in middle cervical-stellate ganglion complex (MC-SG complex) which is considered to control the activity of heart, but not expressed in myocardium. The results also showed that NET expression level in right ganglion was significantly higher than in the left, rendering the greater capacity of NE uptake in right ventricle, a fact which may contribute to the maintenance of right ventricular function under pathologic state.

A post-transplantation lymphoproliferative disease (PTLD) of recipient origin was identified in one of 376 consecutive cases of allogeneic bone marrow transplantation (BMT). This occurred in a 36-year-old woman who received an allogeneic BMT for acute myeloid leukaemia in relapse. At 15 months after BMT, recipient haematopietic and leukaemic cells were found in the bone marrow, which disappeared on withdrawal of immunosuppression. However, severe graft-versus-host disease (GVHD) necessitated the continuation of immunosuppression, leading to the occurrence of PTLD in the liver and lung 12 months afterwards. Fluorescence in situ hybridisation showed that the neoplastic cells were of recipient origin. Although the PTLD also responded completely to withdrawal of immunosuppression, the patient finally died from the complications of GVHD. This case of late onset PTLD post-BMT showed features similar to those in solid organ transplantation, in that the tumour was of recipient origin and responded well to the withdrawal of immunosuppression. Of further interest is that recipient lymphoid regeneration had accompanied autologous haematopoietic regeneration and become a target for subsequent neoplastic transformation.

We describe an ALL patient who developed extensive bone marrow necrosis at the time of relapse 2 months after allogeneic bone marrow transplantation from an HLA-identical sibling. The excruciating and diffuse bone pain, fever and precipitous drop in peripheral blood counts were characteristic. This case illustrates the importance of repeat bone marrow biopsies for the diagnosis of disease relapse and the potential application of MR imaging in the assessment of patients with bone marrow necrosis.

The human norepinephrine transporter (NET) gene was cloned and structurally analyzed. The far 5' fragment containing exon 1 (a non-coding exon) and exon 2 was sequenced. The transcription start site of the gene in human brain stem tissue was determined by primer extension analysis. It was found that the gene could be transcribed from multiple starting points. The 5' flanking sequence contains a proximal G-C rich region, one possible GSG element and several SP1 sites. However it does not contain TATA box and CAAT box motifs. Gel shift analysis with nuclear extracts from different tissues of mouse shows that the G-C rich region may be involved in tissue specific expression of the gene.