Yuan Yow Chiou

Essential role of nephrocystin in photoreceptor intraflagellar transport in mouse

Nephrocystin mutations account for the vast majority of juvenile nephronophthisis, the most common inherited cause of renal failure in children. Nephrocystin has been localized to the ciliary transition zone of epithelial cells or its analogous structure, connecting cilium of retinal photoreceptors. Thus, the retinal degeneration associated with nephronophthisis may be explained by a functional ciliary defect. However, the function of nephrocystin in cilium assembly and maintenance of common epithelial cells and photoreceptors is still obscure. Here, we used Nphp1-targeted mutant mice and transgenic mice expressing EmGFP-tagged nephrocystin to demonstrate that nephrocystin located at connecting cilium axoneme can affect the sorting mechanism and transportation efficiency of the traffic machinery between inner and outer segments of photoreceptors. This traffic machinery is now recognized as intraflagellar transport (IFT); a microtubule-based transport system consisting of motors, IFT particles and associated cargo molecules. Nephrocystin seems to control some of the IFT particle components moving along the connecting cilia so as to regulate this inter-segmental traffic. Our novel findings provide a clue to unraveling the regulatory mechanism of nephrocystin in IFT machinery.

Mouse Kidney Progenitor Cells Accelerate Renal Regeneration and Prolong Survival after Ischemic Injury

Acute tubular necrosis is followed by regeneration of damaged renal tubular epithelial cells, and renal stem cells are supposed to contribute to this process. The purpose of our study is to test the hypothesis that renal stem cells isolated from adult mouse kidney accelerate renal regeneration via participation in the repair process. A unique population of cells exhibiting characteristics consistent with renal stem cells, mouse kidney progenitor cells (MKPC), was isolated from Myh9 targeted mutant mice. Features of these cells include (1) spindle‐shaped morphology, (2) self‐renewal of more than 100 passages without evidence of senescence, and (3) expression of Oct‐4, Pax‐2, Wnt‐4, WT‐1, vimentin, α‐smooth muscle actin, CD29, and S100A4 but no SSEA‐1, c‐kit, or other markers of more differentiated cells. MKPC exhibit plasticity as demonstrated by the ability to differentiate into endothelial cells and osteoblasts in vitro and endothelial cells and tubular epithelial cells in vivo. The origin of the isolated MKPC was from the interstitium of medulla and papilla. Importantly, intrarenal injection of MKPC in mice with ischemic injury rescued renal damage, as manifested by decreases in peak serum urea nitrogen, the infarct zone, and the necrotic injury. Seven days after the injury, some MKPC formed vessels with red blood cells inside and some incorporated into renal tubules. In addition, MKPC treatment reduces the mortality in mice after ischemic injury. Our results indicate that MKPC represent a multipotent adult stem cell population, which may contribute to the renal repair and prolong survival after ischemic injury. STEM CELLS 2010;28:573–584

Targeted disruption of Nphp1 causes male infertility due to defects in the later steps of sperm morphogenesis in mice

Juvenile nephronophthisis type I is the most common genetic disorder causing end-stage renal failure in children and young adults. The defective gene responsible has been identified as NPHP1. Its gene product, nephrocystin-1, is a novel protein of uncertain function that is widely expressed in many tissues and not just confined to the kidney. To gain insight into the physiological function of nephrocystin, Nphp1-targeted mutant mice were generated by homologous recombination. Interestingly, homozygous Nphp1 mutant mice were viable without renal manifestations of nephronophthisis. They appeared normal, but males were infertile with oligoteratozoospermia. Histological analysis of the seminiferous tubules showed that spermatogenesis was blocked at the early stages of spermatid elongation, with degenerating spermatids sloughing off into the lumen. Electron microscopic analysis revealed detachment of early elongating spermatids from Sertoli cells, and a failure of sperm head and tail morphogenesis. However, a few mature spermatozoa were still deposited in the epididymis, though they were frequently dead, immotile, or malformed. These novel findings indicate that nephrocystin is critically required for the differentiation of early elongating spermatids into spermatozoa in mice. The possible roles of nephrocystin in the formation and maintenance of Sertoli-spermatid junctions are still under investigation.

Sleep apnea and the risk of chronic kidney disease: A nationwide population-based cohort study

STUDY OBJECTIVES Sleep apnea (SA) is characterized by apnea during sleep and is associated with cardiovascular diseases and an increase in all-cause mortality. Chronic kidney disease (CKD) is a global health problem that has placed a substantial burden on healthcare resources. However, the relationship between SA and the incidence of CKD is not clear. This study aimed to determine whether SA is an independent risk factor for the development of CKD. DESIGN Retrospective cohort study. SETTING National Health Insurance Research Database (NHIRD) of Taiwan. PATIENTS OR PARTICIPANTS A total of 4,674 adult patients (age ≥ 30 y) in whom SA was newly diagnosed from 2000 to 2010 were included, together with 23,370 non-SA patients as the comparison group. The two groups were frequency-matched for sex, age, and year of receiving medical service. Each individual was followed until 2011. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS These two groups were monitored and observed for the occurrence of CKD. Patients with SA experienced a 1.94-fold increase (95% confidence interval [CI], 1.52-2.46; P < 0.001) in the incidence of CKD, which was independent of sex, age, and comorbid medical conditions. Additionally, they showed a 2.2-fold increase (95% CI, 1.31-3.69; P < 0.01) in the incidence of end-stage renal disease (ESRD). CONCLUSIONS Patients with sleep apnea are at increased risk for chronic kidney disease and end-stage renal disease compared with the general population. As such, screening renal function and treatment of chronic kidney disease is an important issue in patients with sleep apnea.

Personal history and family history as a predictor of gastric cardiac adenocarcinoma risk: A case-control study in Taiwan

OBJECTIVES:To clarify the risk of gastric cardiac adenocarcinoma for patients with a personal and/or family history of gastrointestinal diseases.METHODS:The present study was a hospital-based case-control study conducted from 1992 to 1997 in Kaohsiung, Taiwan, consisting of 176 cases and 579 controls matched by age, sex, and time of hospitalization. With informed oral consent, each subject completed a structured questionnaire during hospitalization regarding sociodemographic status, lifestyle, and health history.RESULTS:The response rate was 98%. Adjusting for age, sex, years of schooling, socioeconomic status, body mass index (BMI), and smoking. Multivariate logistic regression models indicated a reduced effect for patients with a personal history of duodenal ulcer (DU) (odds ratio (OR) = 0.8, 95% confidence interval (CI) 0.5–0.9). No association was observed between the risk of gastric cardiac cancer and other forms of gastric disease. Furthermore, we also demonstrated that individuals with a family history of gastric cancer had a higher risk than those who lacked a family history (OR = 2.5, 95% CI 1.3–4.8).CONCLUSIONS:Our findings provide further evidence that individuals with DU history are less likely to have gastric cardiac cancer, and we infer that Helicobacter pylori (H. pylori) infection (85–95% DU patients infected with H. pylori) alone may not be sufficient to cause gastric cardiac adenocarcinoma. In addition, this study also suggests that a positive family history of gastric cancer may predict an increased risk for the disease.

Lifestyle habits and gastric cancer in a hospital-based case-control study in Taiwan

OBJECTIVES:The aim of this study was to evaluate the effect of lifestyle habits on the risk of primary gastric cancer.METHODS:A hospital-based case-control study of matched pairs was conducted in Kaohsiung, Taiwan, from 1992 to 1996. The study included 649 subjects (152 cases and 497 controls). All subjects were personally interviewed face-to-face by a trained interviewer using a structured questionnaire to collect data about lifestyle. An average of approximately three controls were matched to each case based on age (±3 yr), sex, and time of hospitalization (±2 wk). Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to evaluate results, and a multivariate analysis of the data was performed using a conditional logistic regression model.RESULTS:A significantly elevated risk of contracting gastric cancer was observed in cigarette smokers (OR: 2.7, 95% CI: 1.5–4.3), but not in drinkers of alcoholic beverages (OR: 1.5, 95% CI: 0.9–3.2). A synergistically augmented relationship (multiplication effect) was found between smoking and drinking alcohol for controlling the major confounders. The combined adjusted ORs for all subjects with gastric cancer were 3.0 (95% CI: 1.4–7.1) for current smokers and 1.7 (95% CI: 1.2–4.4) for ex-smokers. Furthermore, a statistically significant positive dose-response trend in gastric cancer was demonstrated based on the age at which smoking was initiated, the duration of the habit, the number of cigarettes smoked per day, and the degree of smoke inhalation. We did not find any association between the other risk factors and gastric carcinogenesis.CONCLUSIONS:Our findings provide further evidence that in Taiwan, cigarette smoking may play the most harmful role in the initial development of gastric cancer, and that drinking alcohol may promote the process.

Adjunctive Oral Methylprednisolone in Pediatric Acute Pyelonephritis Alleviates Renal Scarring

OBJECTIVE: To determine if glucocorticoids can prevent renal scar formation after acute pyelonephritis in pediatric patients. METHODS: Patients younger than 16 years diagnosed with their first episode of acute pyelonephritis with a high risk of renal scar formation (ie, inflammatory volume ≥ 4.6 mL on technetium-99m–labeled dimercaptosuccinic acid scan [DMSA] or abnormal renal ultrasonography results) were randomly assigned to receive either antibiotics plus methylprednisolone sodium phosphate (1.6 mg/kg per day for 3 days [MPD group]) or antibiotics plus placebo (placebo group) every 6 hours for 3 days. Patients were reassessed by using DMSA 6 months after treatment. The primary outcome was the development of renal scars. RESULTS: A total of 84 patients were enrolled: 19 in the MPD group and 65 in the placebo group. Patient characteristics were similar between the 2 groups, including the acute inflammatory parameters and the initial DMSA result. Renal scarring was found in 33.3% of children treated with MPD and in 60.0% of those who received placebo (P < .05). The median cortical defect volumes on follow-up DMSA were 0.0 mL (range: 0–4.5 mL) and 1.5 mL (range: 0–14.8 mL) for the MPD and placebo groups, respectively (P < .01). Patients in the MPD group experienced faster defervescence after treatment than the placebo group. CONCLUSIONS: Adjunctive oral MPD therapy reduced the occurrence and/or severity of renal scarring after acute pyelonephritis in these hospitalized children who had a high risk of renal scar formation.

Retal tubular acidosis complicated with hypokalemic periodic paralysis

Three Chinese girls with hypokalemic periodic paralysis secondary to different types of renal tubular acidosis are presented. One girl has primary distal renal tubular acidosis complicated with nephrocalcinosis. Another has primary Sjogren syndrome with distal renal tubular acidosis, which occurs rarely with hypokalemic periodic paralysis in children. The third has an isolated proximal renal tubular acidosis complicated with multiple organ abnormalities, unilateral carotid artery stenosis, respiratory failure, and consciousness disturbance. The diagnostic evaluation and emergent and prophylactic treatment for these three types of renal tubular acidosis are discussed.

Invasive pneumococcal pneumonia is the major cause of paediatric haemolytic-uraemic syndrome in Taiwan

Aim:  Streptococcus pneumoniae‐associated haemolytic uraemic syndrome (SP‐HUS) is a major concern of paediatric acute renal failure in Taiwan; it leads to significant morbidity and mortality during the acute phase and to long‐term morbidity after an acute episode.

Progressive renal distortion by multiple cysts in transgenic mice expressing artificial microRNAs against Pkd1

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life‐threatening inherited diseases, and the PKD1 gene is responsible for most cases of this disease. Previous efforts to establish a mouse model that recapitulates the phenotypic characteristics of ADPKD, which have used conventional or conditional knockout of the mouse orthologue Pkd1, have been unsuccessful or unreliable. In a previous study, we described the generation of a novel Pkd1 hypomorphic allele, in which Pkd1 expression was significantly reduced but not totally blocked. These Pkd1 homozygous mutant mice rapidly developed renal cystic disease, supporting the hypothesis that ‘haploinsufficiency’ explains development of the ADPKD phenotype. In the present study, we further investigated the Pkd1 haploinsufficiency effect by generating Pkd1 knockdown transgenic mice with co‐cistronic expression of two miRNA hairpins specific to Pkd1 transcript and an Emerald GFP reporter driven by a human ubiquitin B promoter. Two transgenic lines which had ∼60–70% reduction of Pkd1 expression developed severe renal cystic disease at a rate similar to that of human ADPKD. These results further support the haploinsufficiency hypothesis, and suggest that the onset and progression of the renal cystic diseases are correlated with the level of Pkd1 expression. The two novel mutant lines of mice appear to be ideal models for the study of ADPKD. Copyright