Pei-Hsien Lee

MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction

Podocyte dysfunction is a detrimental feature in diabetic nephropathy, with loss of nephrin integrity contributing to diabetic podocytopathy. MicroRNAs (miRs) reportedly modulate the hyperglycemia-induced perturbation of renal tissue homeostasis. This study investigated whether regulation of histone deacetylase (HDAC) actions and nephrin acetylation by miR-29 contributes to podocyte homeostasis and renal function in diabetic kidneys. Hyperglycemia accelerated podocyte injury and reduced nephrin, acetylated nephrin, and miR-29a levels in primary renal glomeruli from streptozotocin-induced diabetic mice. Diabetic miR-29a transgenic mice had better nephrin levels, podocyte viability, and renal function and less glomerular fibrosis and inflammation reaction compared with diabetic wild-type mice. Overexpression of miR-29a attenuated the promotion of HDAC4 signaling, nephrin ubiquitination, and urinary nephrin excretion associated with diabetes and restored nephrin acetylation. Knockdown of miR-29a by antisense oligonucleotides promoted HDAC4 action, nephrin loss, podocyte apoptosis, and proteinuria in nondiabetic mice. In vitro, interruption of HDAC4 signaling alleviated the high glucose-induced apoptosis and inhibition of nephrin acetylation in podocyte cultures. Furthermore, HDAC4 interference increased the acetylation status of histone H3 at lysine 9 (H3K9Ac), the enrichment of H3K9Ac in miR-29a proximal promoter, and miR-29a transcription in high glucose-stressed podocytes. In conclusion, hyperglycemia impairs miR-29a signaling to intensify HDAC4 actions that contribute to podocyte protein deacetylation and degradation as well as renal dysfunction. HDAC4, via epigenetic H3K9 hypoacetylation, reduces miR-29a transcription. The renoprotective effects of miR-29a in diabetes-induced loss of podocyte integrity and renal homeostasis highlights the importance of post-translational acetylation reactions in podocyte microenvironments. Increasing miR-29a action may protect against diabetic podocytopathy.

Hyperuricemia as an independent risk factor of chronic kidney disease in middle-aged and elderly population.

Introduction:Hyperuricemia in the general population remains controversial, in terms of it being considered a risk factor for chronic kidney disease (CKD). Within this context, we evaluated the effects of hyperuricemia on renal function in older Taiwanese adults. Methods:From January 2002 to December 2006, we conducted a community-based medical screening program involving 31,331 subjects older than 40 years. According to the National Kidney Foundation guidelines, stage 3 to 5 patients with CKD were included for analysis. Age, body mass index, systolic blood pressure, fasting plasma glucose, triglyceride, cholesterol and proteinuria were considered potential confounders. Results:Participants with hyperuricemia tended to have higher systolic blood pressure, sugar levels, body mass index, and cholesterol and triglyceride levels but lower estimated glomerular filtration rate (eGFR) levels; eGFR negatively correlated with serum uric acid level. By using multiple logistic regression models before and after adjusting for any confounding factors, we noted that participants with hyperuricemia had a 4.036-fold (odds ratios = 4.036) and 3.649-fold (odds ratios = 3.649) increased risk for CKD, respectively, compared with the control group. We used multiple linear regression analysis to examine the association of serum uric acid level and eGFR at different stages of CKD; significance was found only in participants with stage 3 CKD and not in participants with stages 4 or 5. Conclusions:Hyperuricemia is an independent risk factor for CKD in middle-aged and elderly Taiwanese adults. Thus, an effective screening program that identifies people with hyperuricemia is warranted.

Sustained Wnt/β-catenin signaling rescues high glucose induction of transforming growth factor-β1-mediated renal fibrosis.

Introduction:Although diabetic nephropathy is attributable to transforming growth factor-&bgr;1 (TGF-&bgr;1) overproduction in glomer-ular mesangial cells, the biological role of Wnt/&bgr;-catenin signaling in controlling high glucose-induced TGF-&bgr;1 has not yet been elucidated. Methods:This study found that sustained Wnt/&bgr;-catenin signaling was required to protect glomerular mesangial cells from high glucose induction of TGF-&bgr;1-mediated fibrosis using in vitro and in vivo diabetic models. Results:High glucose down-regulated the Wnt signaling associated with increased TGF-&bgr;1 and fibronectin messenger RNA expression in glomerular mesangial cells. Restoring Wnt4, Wnt5a and cytosolic &bgr;-catenin levels by transfecting Wnt4, Wnt5a and stable &bgr;-catenin alleviated the stimulatory effect of high glucose on c-Jun mediated TGF-&bgr;1 fibrosis. Transfection of kinase-active glycogen synthase kinase-3&bgr; (GSK-3&bgr;) also abrogated high glucose promotion of nuclear c-Jun levels, TGF-&bgr;1 and fibronectin messenger RNA expression in mesangial cells. Pharmacological modulation of GSK-3&bgr;&bgr; and &bgr;&bgr;-catenin signaling by recombinant Wnt5a or GSK-3&bgr; inhibitor (BIO or LiCl) suppressed high glucose promotion of TGF-&bgr;1-mediated fibrosis. Exogenous BIO and SB216763 alleviated TGF-&bgr;1-mediated fibrogenic expression in the kidneys of diabetic rats. Immunohistochemistry showed that GSK-3&bgr; inhibitor significantly reversed the diabetic attenuation of TGF-&bgr;1 and c-Jun coinciding with fibronectin immunoreactivity within glomeruli. Immunofluorescence demonstrated that cells within the glomeruli restored &bgr;-catenin expression after BIO and SB216763 treatment in cells within diabetic glomeruli colocalized with fragmented nuclei by 4′,6-diamidino-2-phenylindole staining. Conclusions:Sustained Wnt signaling reduced c-Jun-dependent TGF-&bgr;1-mediated fibronectin accumulation in mesangial cells. These findings suggest that modulation of Wnt signaling is a viable alternative strategy to rescue the TGF-&bgr;1-mediated fibrotic signaling pathway in diabetic renal injury.

Hypertriglyceridemia: an independent risk factor of chronic kidney disease in Taiwanese adults.

Background:The prevalence and incidence of chronic kidney disease (CKD) are relatively high in Taiwanese patients than in patients of other countries, particularly in the older age groups. Dyslipidemia in patients with CKD has been recognized as a risk factor for disease progression but the role of triglycerides (TGs) remains controversial. With this regard, we evaluated the effects of hypertriglyceridemia on renal function in Taiwanese adults (aged ≥40 years). Methods:From January 2002 to December 2006, we conducted a community-based medical screening program in Chiayi County with 18,422 subjects (aged ≥40 years). The CKD was defined as an estimated glomerular filtration rate of <60 mL min 1.73 m2. Age, body mass index, systolic blood pressure, fasting plasma glucose, and serum total cholesterol were considered as potential confounders. Result:The CKD was prevalent in 24.2% of the middle-aged and elderly population. By using multiple logistic regression models, we determined that old age and elevated levels of body mass index, systolic blood pressure, fasting plasma glucose, and cholesterol were associated with CKD. The adjusted odds ratios of CKD in participants with serum TG ≧200 mg/dL was 1.901 (95% confidence interval: 1.07–3.36; P < 0.05) and in participants with serum TG > 500 mg/dL it increased to 2.205 (1.33–3.64, P < 0.05). Conclusion:Hypertriglyceridemia is an independent risk factor for CKD in Taiwanese adults. Thus, an effective screening program that identifies people with hypertriglyceridemia is warranted.

Hyperuricemia Is an Independent Risk Factor for New Onset Micro-Albuminuria in a Middle-Aged and Elderly Population: A Prospective Cohort Study in Taiwan

Background Hyperuricemia is now regarded as a risk factor for cardiovascular disease. Micro-albuminuria is associated with increased risk for cardiovascular disease and chronic kidney disease. We hypothesized that elevated serum uric acid (UA) is associated with development of micro-albuminuria in the general population. Methodology/Principal Findings We conducted a community-based prospective cohort study. A total of 1862 subjects from southern Taiwan, all older than 40 years, were screened and 993 of these participants without micro-albuminuria were followed for 4 years. Urinary albumin-to-creatinine ratio was measured two times per year. A multiple linear regression model indicated that serum UA was independently associated with ln(ACR) after adjustment for 8 factors (age, sex, and 6 metabolic metrics) (β = 0.194, p<0.01). Logistic regression analysis indicated that each 1 mg/dL increase of UA was associated with a 1.42-fold increased risk of micro-albuminuria after adjustment for the same 8 factors (OR = 1.42, 95% CI: 1.27–1.59, p<0.01). A Cox regression model using subjects with serum UA less than 5 mg/dL as reference group indicated higher hazard ratios (HRs) only found in subjects with serum UA more than 7 mg/dL (HR = 3.54, 95% CI: 2.11–5.93, p<0.01) and not in subjects with serum UA of 5 to 7 mg/dL (HR = 1.30, 95% CI: 0.82–2.07, p = 0.15). Conclusion Hyperuricemia is significantly associated with micro-albuminuria in middle-aged and elderly males and females from a general population in Taiwan. Elevated serum UA is an independent predictor for development of micro-albuminuria in this population.

Cannabinoid receptor 1 disturbance of PPARγ2 augments hyperglycemia induction of mesangial inflammation and fibrosis in renal glomeruli.

Intensive fibrosis in the glomerular microenvironment is a prominent feature of diabetic nephropathy. Cannabinoid receptor 1 (CB1R) reportedly mediates diabetes-induced renal injury. However, studies on the molecular events underlying CB1R promotion of renal dysfunction are limited. This study is undertaken to investigate whether CB1R signaling via Ras or PPARγ pathway regulates mesangial fibrosis in diabetic kidneys. In streptozotocin-induced diabetic rats, hyperglycemia induced glomerular hypertrophy and fibrosis in association with increased IL-1β, fibronectin, and CB1R expressions and reduced PPARγ2 signaling. CB1R transgenic mice gained kidney weight, and renal glomeruli strongly displayed IL-1β and fibrotic matrices. Disruption of CB1R by antisense oligonucleotides or inverse agonist AM251 restored PPARγ2 signaling and reduced the promotional effects of hyperglycemia on the expression of fibrogenic transcription factor c-Jun, inflammation regulator SOCS3, proinflammatory cytokines, and accumulation of fibrotic matrix. PPARγ agonist rosiglitazone reduced the hyperglycemia-mediated enhancement of CB1R signaling, inflammation, and glomerular fibrosis in diabetic animals. In vitro, CB1R antagonism restored PPARγ2 action and reduced the promotional effects of high glucose on Ras, ERK, c-Jun, SOCS3 signaling, IL-1β, and fibronectin expression in renal mesangial cells. Activation of PPARγ2 reduced the high glucose-induced CB1R expression in mesangial cells. Taken together, CB1R signaling contributes to the hyperglycemia disturbance of PPARγ2 signaling and increases inflammatory cytokine secretion and fibrotic matrix deposition in renal glomeruli. CB1R mediates the hyperglycemia-induced inflammation and fibrosis in mesangial cells by regulating Ras, ERK, and PPARγ2 signaling. CB1R blockade has a therapeutic potential to reduce the deleterious actions of hyperglycemia on renal glomerular integrity.Key messageHyperglycemia increases glomerular fibrosis, inflammation, and CB1R signaling.CB1R signaling promotes fibrosis and inflammation of renal tissue.Loss of CB1R function alleviates diabetes-mediated renal deterioration.PPARγ agonist decreases CB1R expression in diabetic renal glomeruli.Ras and ERK mediated CB1R promotion of fibrosis matrix deposition in mesangial cells.

Nitric oxide donors rescue diabetic nephropathy through oxidative-stress- and nitrosative-stress-mediated Wnt signaling pathways

The role of the renal nitric oxide (NO) system in the pathophysiology of diabetic nephropathy constitutes a very challenging and fertile field for future investigation. The purpose of the present study was to investigate whether NO donors can attenuate diabetic renal fibrosis and apoptosis through modulating oxidative‐ and nitrosative‐stress, and Wnt signaling using in vivo diabetic models.

Analgesic use, parents' clan, and coffee intake are three independent risk factors of chronic kidney disease in middle and elderly-aged population: a community-based study.

Abstract Chronic kidney disease (CKD) is a world-wide public health problem. The purpose of this study was to identify the role of some controversial potential risk factors in development of CKD. “Community Complex Health Screening” is a large-scale, free, health program for individuals ≥40 years of age that has been available since January 2002 in Chiayi County, Taiwan. A questionnaire was administered to study participants, collecting information on ethnicity, use of analgesics, and life habits. Age, sex, and blood biochemical analyses were considered as potential confounders. A high prevalence and low awareness of CKD were noted in this population. Females with CKD had a lower awareness of their illness than males. Analgesic users had a significantly lower estimated glomerular filtration rate (eGFR). Age (OR = 1.095), females (OR = 0.348), fasting plasma glucose (OR = 1.005), level of uric acid (UA) (OR = 1.517), and analgesic usage (OR = 1.512) remained independent predictors of CKD. Multivariate linear regression found that use of analgesics, father’ clan from Fujian, mother’ clan from Fujian, and coffee intake were independent determinants of renal outcome with coefficient of regression (β) of −0.102, −0.192, 0.210 and 0.88, respectively. The prevalence of CKD decreased with advanced education. Further, there was no significant difference between education background and analgesics use. In conclusion, analgesic use, parents’ clan, and coffee intake were independent risk factors for CKD in middle-aged and elderly Taiwanese. Thus, an effective educational program that increases the awareness of such individuals residing in rural counties is warranted.

Educational Intervention in CKD Retards Disease Progression and Reduces Medical Costs for Patients with Stage 5 CKD

Background: Nephrologist-based multidisciplinary care (MDC) has a positive impact on slowing chronic kidney disease (CKD) progression. However, the benefits of MDC in patients with stage 5 CKD remain unclear. Methods: Stage 5 CKD patients who visited the Chang Gung Memorial Hospital, Chiayi, Taiwan during the period of 2002–2008 were enrolled. The incident dialysis and medical cost were compared between MDC recipients and nonrecipients. The MDC recipients were divided into two groups by educational duration to observe the clinical renal outcome and medical care expenses. The effect of MDC on renal disease progression was also compared in MDC recipients with and without diabetes. Results: Out of 307 patients, 171 received MDC. For MDC recipients, the temporary usage of catheter was reduced (54.7% vs. 79.4%, p < 0.001), the hospital stay was shorter (18.64 ± 1.20 vs. 24.63 ± 1.22 months, p = 0.001), and the total medical cost was lower [New Taiwan dollars (NTD) 105,948.54 ± 9,967.22 vs. NTD 160,388.61 ± 16,373.97, p = 0.005] than for nonrecipients. Out of the 171 MDC recipients, those with MDC for more than 1 year had slower renal disease progression (0.76 ± 0.27 mL/min per 1.73 m2 per year) and had an estimated per- capita annual cost savings of about NTD 336,500.66. MDC recipients with diabetes had a higher risk of requiring dialysis than those without diabetes. Conclusions: MDC could significantly reduce temporary use of the catheter, hospital stay, and total medical costs in patients with stage 5 CKD. Furthermore, longer (>1 year) MDC could preserve renal function and deliver annual medical cost savings.

Metabolic Syndrome as an Independent Risk Factor of Chronic Kidney Disease in Southern Taiwan

BACKGROUND: Chronic kidney disease (CKD) is an important and noteworthy health issue worldwide. It is especially a problem in Taiwan because of its high prevalence and incidence. Metabolic syndrome is associated with CKD, but the mechanisms underlying this association have not been determined. In view of this, we evaluated the relationship between CKD and metabolic syndrome beyond the components of metabolic syndrome and characteristics of Taiwanese adults aged 40 years and above.METHODS: From January 2002 to December 2006, we conducted a community-based medical screening program in Chiayi County of 21,619 subjects aged 40 years and above. According to the National Kidney Foundation guidelines, subjects were considered to have CKD in our study if their estimated glomerular filtration rates were lower than 60 mL/min per 1.73 m2. Age, gender, and components of metabolic syndrome, including body mass index (BMI), systolic blood pressure, fasting plasma glucose, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were considered potential confounders.RESULTS: Participants with metabolic syndrome were significantly more likely to have CKD than those without metabolic syndrome (29.3% and 19.6%, respectively; P ＜ 0.001). Multiple logistic regression models determined that old age, female gender, and metabolic syndrome were independent risk factors of CKD. The risk of CKD was significantly proportional to the number of metabolic syndrome components. Compared with those without metabolic syndrome, participants with two components of metabolic syndrome had a 1.407-fold (95% confidence interval [CI], 1.256-1.575; P ＜ 0.001) increased risk while those with more than three components had a 1.695-fold (95% CI, 1.497-1.919; P ＜ 0.001) increased risk of CKD. Higher BMI, lower HDL-C levels, and higher TG levels were significantly associated with an increased risk of CKD.CONCLUSIONS: Metabolic syndrome is an independent risk factor for CKD in Taiwanese adults. Therefore, an effective screening program for early detection of people with metabolic syndrome is required.