NDUFS4 Regulates Cristae Remodeling in Diabetic Kidney Disease

The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generated diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model to investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that these conditional mice exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping proteins in linking NDUFS4 with improved cristae morphology. Taken together, we discover the central role of NDUFS4 as a powerful regulator of cristae remodeling, respiratory supercomplexes assembly, and mitochondrial ultrastructur

High Prevalence of Hyperhomocysteinemia and Its Association with Target Organ Damage in Chinese Patients with Chronic Kidney Disease

Hyperhomocysteinemia (HHcy) is recognized as a risk factor for cardiovascular disease. However, the prevalence of HHcy and its role in association with target organ damage in patients with chronickidney disease (CKD) are not well understood. This cross-sectional study included 1042 CKD patients who were admitted to our hospital. Patients were divided into two groups: hyperhomocysteinemia and normohomocysteinemia. Multivariable linear regression analyses were used to evaluate the association between plasma homocysteine and renal/cardiovascular parameters. The prevalence of HHcy in patients with CKD was 52.78%, and the prevalence in CKD stage 1, stage 2, stage 3, stage 4 and stage 5 patients was 10.73%, 29.22%, 58.71%, 75.23% and 83.75%, respectively. Patients with HHcy had higher incidences of renal damage, left ventricular hypertrophy, left ventricular diastolic dysfunction and abnormal carotid intima-media thickness compared with patients with normohomocysteinemia (p < 0.05), while multivariable linear regression analyses showed plasma homocysteine was only associated with the estimated glomerular filtration rate (eGFR). eGFR, uric acid, albumin, gender, hemoglobin and calcium×phosphate were associated with levels of plasma homocysteine in these CKD patients. The prevalence of HHcy in Chinese patients with CKD was high, and serum homocysteine levels were associated with impaired renal function in these patients

Activation of the Nrf2-ARE Pathway Attenuates Hyperglycemia-Mediated Injuries in Mouse Podocytes

Background: Damage to podocytes caused by excessive reactive oxygen species (ROS) contributes to onset and progression of diabetic kidney disease (DKD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a redox-sensing transcription factor that can induce the expression of antioxidant enzymes. We explored whether activation of Nrf2 pathway attenuated hyperglycemia-induced injuries in mouse podocytes. Methods: Tert-Butylhydroquinone (tBHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression. Apoptosis and intracellular superoxide anion production were measured by flow cytometry. The activity of the Nrf2 antioxidant pathway was measured by an antioxidant response element (ARE)-driven luciferase reporter gene assay, and Nrf2 expression was assessed by real-time PCR and western blot analyses. Results: Podocytes incubated with high-glucose (HG) medium had higher intracellular superoxide anion and hydrogen peroxide production, higher apoptosis rate, higher bovine serum albumin (BSA) permeability and lower synaptopodin expression compared with podocytes exposed normal glucose (NG) (pppConclusions: Our findings suggest that protection against activation of the Nrf2-ARE pathway in podocytes exposed to hyperglycemia. Thus, regulation of the Nrf2-ARE pathway could be a therapeutic option to combat oxidative stress and inhibit the development of DKD

Nighttime Systolic Blood-Pressure Load Is Correlated with Target-Organ Damage Independent of Ambulatory Blood-Pressure Level in Patients with Non-Diabetic Chronic Kidney Disease.

The impacts of blood pressure (BP) load on target-organ damage in patients with chronic kidney disease (CKD) are largely unclear. We examined whether BP load is correlated with target-organ damage (TOD) in Chinese CKD patients independent of BP level.We recruited 1219 CKD patients admitted to our hospital division in this cross-sectional study. The TOD were measured by estimated glomerular filtration rate (eGFR), proteinuria, left ventricular mass index (LVMI) and carotid intima-media thickness (cIMT) in this study. Univariate and multivariate linear analyses were used to evaluate the relationship between systolic blood pressure (SBP) load, diastolic blood pressure (DBP) load and these renal, cardiovascular parameters.In multivariable-adjusted models, BP load and ambulatory BP levels both independently correlated with LVMI, eGFR and proteinuria in all groups of CKD patients (p<0.05), 24-h SBP correlated with cIMT only in non-diabetic CKD patients without hypertension (p<0.05), while nighttime SBP load was associated with cIMT only in non-diabetic CKD patients (p<0.05). Furthermore, nighttime SBP load additionally increased coefficient of determination (R(2)) and correlated with LVMI, proteinuria in non-diabetic CKD patients without hypertension (R(2) = 0.034, P<0.001 and R(2) = 0.012, P = 0.006 respectively) and LVMI, cIMT, eGFR in non-diabetic CKD patients with hypertension (R(2)>0.008, P<0.05) in multivariable-adjusted model which already including the 24-h BP. BP load did not refine this correlation based on the 24-h BP level in diabetic CKD patients.Night-time SBP load was correlated with TOD in patients with non-diabetic chronic kidney disease independent of BP level

Reversed dipper blood-pressure pattern is closely related to severe renal and cardiovascular damage in patients with chronic kidney disease.

BACKGROUND: A non-dipper blood pressure (BP) pattern is very common in chronic kidney disease (CKD) patients and affects the progression and development of cardiovascular disease. However, data on the reversed dipper BP pattern on target-organ damage in Chinese CKD patients are lacking. METHODS: A total of 540 CKD patients were enrolled. Ambulatory blood pressure monitoring (ABPM), clinical BP, ultrasonographic assessment and other clinical data were collected. Univariate and multivariate analyses were used to ascertain the relationship between ABPM results and clinical parameters. RESULTS: A total of 21.9% CKD patients had a reversed dipper BP pattern, 42% of patients had a non-dipper BP pattern and 36.1% of patients had a dipper BP pattern. Patients with reversed dipper BP pattern had the worst renal function and most severe cardiovascular damages among these CKD patients (p<0.05). The estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) correlated significantly with the rate of decline of nocturnal BP. A reversed dipper BP pattern was an independent factor affecting kidney damage and left ventricular hypertrophy. Age, lower hemoglobin level, higher 24-h systolic BP from ABPM, and higher serum phosphate levels were independent associated with a reversed dipper BP pattern after multivariate logistic regression analyses. CONCLUSION: The reversed dipper BP pattern is closely related to severe renal damage and cardiovascular injuries in CKD patients, and special attention should be given to these CKD patients

Simvastatin alleviates hyperpermeability of glomerular endothelial cells in early-stage diabetic nephropathy by inhibition of RhoA/ROCK1.

Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy (DN). There is increasing evidence that dysfunction of the endothelial tight junction is a crucial step in the development of endothelial hyperpermeability, but it is unknown whether this occurs in glomerular endothelial cells (GEnCs) during the progression of DN. We examined tight junction dysfunction of GEnCs during early-stage DN and the potential underlying mechanisms. We also examined the effect of simvastatin (3-Hydroxy-3-methylglutaryl CoA reductase inhibitor) on dysfunction of the tight junctions of cultured GEnCs and in db/db mice with early-stage DN.We assessed the expression of occludin and ZO-1, two major components of the tight junction complex, in cultured rat GEnCs treated with high glucose and in 12 week-old db/db mice with early-stage DN. We also investigated activation of RhoA/ROCK1 signaling, GEnC permeability, and renal function of the mice.High glucose suppresses occludin expression and disrupts occludin/ZO-1 translocation in GEnCs. These changes were associated with increased permeability to albumin and activation of RhoA/ROCK1 signaling. Occludin and ZO-1 dysregulation also occurred in the glomeruli of mice with early-stage DN, and these abnormalities were accompanied by albuminuria and activation of RhoA/ROCK1 in isolated glomeruli. Simvastatin prevented high glucose or hyperglycemia-induced dysregulation of occludin and ZO-1 by inhibition of RhoA/ROCK1 signaling in cultured GEnCs and in db/db mice with early-stage DN.Our results indicate that activation of RhoA/ROCK1 by high glucose disrupts the expression and translocation of occludin/ZO-1 and that simvastatin alleviates occludin/ZO-1 dysregulation and albuminuria by suppressing RhoA/ROCK1 signaling during early-stage DN. These results suggest a potential therapeutic strategy for preventing the onset of albuminuria in early-stage DN

High Prevalence of Hyperhomocysteinemia and Its Association with Target Organ Damage in Chinese Patients with Chronic Kidney Disease

Hyperhomocysteinemia (HHcy) is recognized as a risk factor for cardiovascular disease. However, the prevalence of HHcy and its role in association with target organ damage in patients with chronickidney disease (CKD) are not well understood. This cross-sectional study included 1042 CKD patients who were admitted to our hospital. Patients were divided into two groups: hyperhomocysteinemia and normohomocysteinemia. Multivariable linear regression analyses were used to evaluate the association between plasma homocysteine and renal/cardiovascular parameters. The prevalence of HHcy in patients with CKD was 52.78%, and the prevalence in CKD stage 1, stage 2, stage 3, stage 4 and stage 5 patients was 10.73%, 29.22%, 58.71%, 75.23% and 83.75%, respectively. Patients with HHcy had higher incidences of renal damage, left ventricular hypertrophy, left ventricular diastolic dysfunction and abnormal carotid intima-media thickness compared with patients with normohomocysteinemia (p &lt; 0.05), while multivariable linear regression analyses showed plasma homocysteine was only associated with the estimated glomerular filtration rate (eGFR). eGFR, uric acid, albumin, gender, hemoglobin and calcium×phosphate were associated with levels of plasma homocysteine in these CKD patients. The prevalence of HHcy in Chinese patients with CKD was high, and serum homocysteine levels were associated with impaired renal function in these patients

Advanced glycation end-products activate the renin-angiotensin system through the RAGE/PI3-K signaling pathway in podocytes

Purpose: The purpose of this study was to investigate the effects of advanced glycation end-products (AGEs) on the components of the renin-angiotensin system (RAS) in podocytes and to understand the mechanism of these effects. Methods: Immortalized mouse podocytes were exposed to various concentrations of AGEs for different time intervals. The expression levels of angiotensinogen (AGT), angiotensin II type 1 and 2 receptors (AT1R and AT2R) and renin were examined by real-time PCR and western blot; the receptor for AGEs (RAGE) and both Akt and phosphorylated Akt were examined by western blot; levels of angiotensin II (Ang II) were assayed by ELISA, and the activity of angiotensin-converting enzyme (ACE) was evaluated by measuring the production of hippuric acid in vitro. Results: Treatment with AGEs resulted in significant increases in the expression of AGT (62%, P=0.002) and AT1R (59%, P=0.01). Moreover, Ang II levels increased significantly in both cell lysates (70%, P=0.018) and conditioned media (65%, P=0.01). ACE activity was also significantly higher in cell lysates (68% , P= 0.035) and conditioned media (65%, P=0.023). There were no changes in renin or AT2R expression (P > 0.05). AGEs did increase the expression of RAGE by 50% (P=0.012) and the phosphorylation of Akt by 100% (P=0.001). When podocytes were pretreated with anti-RAGE antibody (50 µg/ml) or the phosphoinositide 3-kinase (PI3-K) inhibitor, LY294002 (10 µM), the AGEs-induced increases in AGT and AT1R expression were reduced. Likewise, Ang II levels and ACE activity decreased significantly. Conclusion: AGEs activate the RAS in podocytes through the RAGE-PI3-K/Akt-dependent pathway and lead to an increase in podocyte apoptosis