Identification of proteins related to SIS3 by iTRAQ and PRM-based comparative proteomic analysis in cisplatin-induced acute kidney injury.

Background: Cisplatin is a commonly used nephrotoxic drug and can cause acute kidney injury (AKI). In the present study, isobaric tags for relative and absolute quantification (iTRAQ) and parallel reaction monitoring (PRM)-based comparative proteomics were used to analyze differentially expressed proteins (DEPs) to determine the key molecular mechanism in mice with cisplatin-induced AKI in the presence or absence of SIS3, a specific p-smad3 inhibitor, intervention. Methods: The cisplatin-induced AKI mouse model was established and treated with SIS3. We used iTRAQ to search for DEPs, PRM to verify key DEPs and combined Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for bioinformatics analysis. We then assessed lipid deposition, malondialdehyde (MDA) and reactive oxygen species (ROS) and detected the expression of SREBF1, SCD1, CPT1A, PPARα and NDRG1 in vitro. Results: Proteomic analysis showed that the identified DEPs were mainly enriched in energy metabolism pathways, especially in lipid metabolism. When SIS3 was applied to inhibit the phosphorylation of Smad3, the expression of NDRG1 and fatty acid oxidation key proteins CPT1A and PPARα increased, the expression of lipid synthesis related proteins SREBF1 and SCD1 decreased and the production of lipid droplets, MDA and ROS decreased. Conclusion: SIS3 alleviates oxidative stress, reduces lipid accumulation and promotes fatty acid oxidation through NDRG1 in cisplatin-induced AKI. Our study provides a new candidate protein for elucidating the molecular mechanisms of fatty acid metabolism disorders in cisplatin-induced acute kidney injury.

SIS3 Alleviates Cisplatin-Induced Acute Kidney Injury by Regulating the LncRNA Arid2-IR-Transferrin Receptor Pathway.

INTRODUCTION: TGF-ß/Smad3 may be involved in the pathogenesis of acute kidney injury (AKI), but its functional role and mechanism of action in cisplatin-induced AKI are unclear. Here, we established a cisplatin-induced AKI mouse model to demonstrate that Smad3 may have roles in cisplatin nephropathy because of its potential effects on tubular epithelial cell (TEC) death and regeneration. METHODS: Using a cisplatin-induced AKI model, the expression levels of lncRNA Arid2-IR were measured by qRT-PCR and the location detected by FISH. Transfected with overexpression of lncRNA Arid2-IR by lentiviral vector in TECs, and the expression of cleaved caspase 3, Bax, Bcl-2, PCNA, p21, p27, transferrin receptor (TFRC), FTH, and FTL were measured by Western blot. Protein molecules bound to lncRNA Arid2-IR were identified by RIP, RNA pull-down assay, mass spectrometry. RESULTS: LncRNA Arid2-IR was significantly downregulated in vivo and in vitro. SIS3 decreased cell apoptosis and promoted cell regeneration by upregulating lncRNA Arid2-IR expression. LncRNA Arid2-IR regulated the cell cycle by decreasing expression of the cyclin-dependent kinase inhibitors p21 and p27. Finally, lncRNA Arid2-IR interacted with the TFRC, and overexpression of lncRNA Arid2-IR increased TFRC expression and decreased FTH and FTL. CONCLUSION: Smad3 regulated lncRNA Arid2-IR via TFRC, thereby regulating the cell cycle, protecting against cell apoptosis, and promoting cell regeneration.

Diabetic Kidney Disease versus Primary Glomerular Disease: A Propensity Score-Matched Analysis of Association between Ambulatory Blood-Pressure Monitoring and Target-Organ Damage.

Diabetic kidney disease (DKD) and primary glomerular disease (PGD) are the main causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). This study was conducted to compare the characteristics of ambulatory blood-pressure monitoring (ABPM) and its relationship with target-organ damage (TOD) in patients with DKD and PGD matched by propensity score. The assessment of TOD included macroalbuminuria, left ventricular hypertrophy (LVH) and macrovascular disease. Propensity-score weighting (PSW) was used in stratified analysis. Results: Patients with DKD had a higher prevalence of abnormal blood-pressure patterns such as reversed dipper pattern, nocturnal hypertension, and sustained hypertension and had a higher prevalence of TOD than did patients with PGD. Logistic regression indicated that patients with DKD were more related to TOD than to PGD. The stratified analysis indicated that DKD patients with white-coat hypertension, masked hypertension and sustained hypertension had closer relationships with TOD compared with PGD patients. Conclusion: Patients with type 2 diabetic kidney disease had more abnormal blood-pressure patterns and were more closely related to target organ damage than were patients with primary glomerular disease.

Lower ambulatory nocturnal SBP is associated with less cardiovascular and renal damage in normotensive hospitalized patients with chronic kidney disease.

OBJECTIVE: The impact of nocturnal blood pressure (BP) on target organ damage (TOD) in chronic kidney disease (CKD) patients with normotension has not been established. In this study, we determined whether nocturnal BP is correlated with cardiovascular and renal damage independent of the 24-h BP in CKD patients with normotension or hypertension. METHODS: A total of 1166 hospitalized patients with CKD not requiring dialysis were enrolled in this cross-sectional study, 421 and 745 of whom had normotension and hypertension, respectively. TOD was assessed by the left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR) and presence of proteinuria. Univariate and multivariable regression analyses were used to evaluate the relationships between nocturnal BP and TOD. RESULTS: In the multivariable-adjusted models, including the 24-h BP, nocturnal SBP was independently associated with the LVMI, eGFR and proteinuria in patients with normotension (P < 0.05), while the nocturnal DBP was not correlated with proteinuria. The nocturnal SBP was associated with LVMI and proteinuria, but not the eGFR in patients with hypertension. We did not demonstrate an association between nocturnal DBP and TOD in these patients. When nocturnal SBP in patients with normotension was further divided into tertiles [tertile 1 (<104 mmHg), tertile 2 (104-114 mmHg) and tertile 3 (≥114 mmHg)], multivariate analysis showed that tertile 3 was independently associated with TOD. CONCLUSION: Nocturnal SBP was shown to be an independent risk factor for TOD in patients with normotension. Targeting a nocturnal ambulatory SBP to less than 114 mmHg or even less than 104 mmHg may help prevent TOD in patients with CKD.

Different effects of morning and nocturnal hypertension on target organ damage in chronic kidney disease.

Both morning hypertension (MH) and nocturnal hypertension (NH) are associated with severe target organ damage in patients with chronic kidney disease (CKD). However, the isolated or combined effects of MH and NH on target organ damage are less well-defined. A cross-sectional study was conducted among 2386 non-dialysis CKD patients with ambulatory blood pressure monitoring. The authors categorized patients into four groups based on the presence or absence of MH and NH. Multivariate logistic analyses were used to evaluate the correlation between hypertension subtypes and target organ damage, including left ventricular hypertrophy (LVH), abnormal carotid intima-media thickness (CIMT), low estimated glomerular filtration rate (eGFR), and albuminuria. The percentages of isolated MH, isolated NH, and combined MH and NH were 2.3%, 24.0%, and 49.3%, respectively. Compared to patients without MH and NH, isolated MH was only related to low eGFR (2.26 [95% confidence interval: 1.00-5.09]) and albuminuria (2.17 [95% CI: 1.03-4.54]). Meanwhile, combined MH and NH group compared to the group without MH and NH had a higher risk of LVH (2.87 [95% CI: 2.01-4.09]), abnormal CIMT (2.01 [95% CI: 1.47-2.75]), low eGFR (3.18 [95% CI: 2.23-4.54]), and albuminuria (1.79 [95% CI: 1.33-2.40]), even in patients without daytime hypertension. The risk of cardiovascular and renal damage was also observed in the isolated NH group. In conclusion, morning hypertension is associated with kidney dysfunction and has combined effects with nocturnal hypertension on cardiovascular damage in chronic kidney disease patients.

Effect of age and isolated systolic or diastolic hypertension on target organ damage in non-dialysis patients with chronic kidney disease.

The aim of this study was to investigate associations between age-dependent variations in isolated systolic/diastolic hypertension (ISH/IDH) with target organ damage in chronic kidney disease (CKD). A cross-sectional study was conducted among 2,459 CKD patients with ambulatory blood pressure monitoring. Blood pressure was categorized into four groups: normotension, ISH, IDH, and systolic-diastolic hypertension. The outcome measurements were left ventricular mass index (LVMI), estimated glomerular filtration rate(eGFR), and urinary albumin creatinine ratio (ACR). Older patients (≥60-years-old) had a higher prevalence of ISH and a lower prevalence of IDH than younger patients (<60-years-old). In multivariate analysis, compared with the normotension group, younger patients with ISH were associated with higher LVMI (+14.4 g/m2), lower eGFR (-0.2 log units), and higher ACR (+0.5 log units); but younger patients with IDH were only associated with lower eGFR (-0.2 log units) and higher ACR (+0.4 log units). Among older patients, ISH was correlated with higher LVMI (+8.8 g/m2), lower eGFR (-0.2 log units), and higher ACR (+1.0 log units), whereas IDH was not associated with these renal/cardiovascular parameters. In conclusion, ISH was associated with a relatively high risk of target organ damage irrespective of age, whereas IDH was only correlated with renal injury in younger CKD patients.

A retrospective cohort study on the pathology and outcomes of type 2 diabetic patients with renal involvement.

OBJECTIVE: To investigate the association of clinical and histological characteristics and the development of ESRD in T2DM patients with renal involvement. METHODS: We conducted a retrospective analysis of clinical and pathologic data from T2DM patients who underwent renal biopsy (n = 120). RESULTS: The mean age, duration of diabetes, and eGFR were 50.9 ± 11.2 years, 92.8 ± 41.3 months, 55.1 ± 42.3 mL/min/1.73 m2, respectively. Among these patients, 57 (47.5%) were diagnosed with diabetic nephropathy (DN), and 63 (52.5%) with non-diabetic renal disease (NDRD). The most common subtype of NDRD is membranous nephropathy. Compared with the NDRD group, the DN group had a longer duration of diabetes, worse renal function, and a higher proportion of diabetic retinopathy. Kaplan-Meier analysis showed that the 5-year renal survival rate of the DN group was only 41%, whereas that of the NDRD group was 84%. ESRD was defined as eGFR below 15 mL/min/1.73 m2. After multivariate adjustment, the risk of ESRD in DN patients was 3.81 times higher than that in NDRD patients. According to Glomerular Class, the 5-year renal survival rate of type IIA, IIB, III, and IV in the DN group was 88, 56, 28, and 15%, respectively. Kaplan-Meier analysis showed that there was a significant difference in renal survival among different glomerular classes or different interstitial fibrosis and tubular atrophy (IFTA) scores. But Cox proportional hazards analysis indicated that only IFTA score (HR 2.75, 95% CI 1.37-5.51, P = 0.001), but not the glomerular class (HR 1.21, 95% CI 0.73-2.00, P = 0.465), could predict renal outcome when adjusting for multivariate. CONCLUSION: The prognosis of DN patients is significantly worse than that of NDRD patients. Compared with glomerular lesions, tubulointerstitial lesions were associated with higher risk for renal death in DN patients.

Ambulatory blood pressure is better associated with target organ damage than clinic blood pressure in patients with primary glomerular disease.

BACKGROUND: Blood pressure is an important and modifiable cardiovascular risk factor. Ambulatory blood pressure monitoring (ABPM) provides valuable prognostic information in patients with chronic kidney disease (CKD), yet little is known about the association of various types of BP measurements with target organ damage (TOD) in patients with primary glomerular disease. The goal of this study was to investigate whether ambulatory blood pressure is better associated with TOD than clinic blood pressure in patients with primary glomerular disease. METHODS: 1178 patients with primary glomerular disease were recruited in this cross-sectional study. TOD were assessed by the following 4 parameters: left ventricular mass index (LVMI or LVH, left ventricular hypertrophy), estimated glomerular filtration rate (eGFR< 60 ml/min/1.73m2), albumin-to-creatinine ratio (ACR ≥ 30 mg/g) and carotid intima-media thickness (cIMT) or plaque. Receiver operating characteristic (ROC) curve and multivariate logistic regression analyses were used to evaluate the relationship between ambulatory or clinic systolic blood pressure (SBP) indexes and TOD. RESULTS: Among 1178 patients (mean age, 39 years,54% men), 116, 458, 1031 and 251 patients had LVH, eGFR < 60 ml/min/1.73m2, ACR ≥ 30 mg/g and cIMT≥0.9 mm or plaque respectively. Area under ROC curves for TOD in ambulatory SBP, especially nighttime SBP, was greater than that in clinic SBP (P < 0.05). Multivariate logistic regression analyses showed that 24 h SBP, daytime SBP and nighttime SBP were significantly associated with LVH, eGFR< 60 ml/min/1.73m2 and ACR ≥ 30 mg/g after adjustment for clinic SBP, while the association of clinic SBP was attenuated after further adjustment for nighttime SBP. CONCLUSIONS: Ambulatory blood pressure, especially nighttime blood pressure, is probably superior to clinic blood pressure and has a significant association with TOD in primary glomerular disease patients.

The difference between nocturnal dipping status and morning blood pressure surge for target organ damage in patients with chronic kidney disease.

The authors aimed to investigate the epidemiology of morning blood pressure (BP) surge (MBPS) in chronic kidney disease (CKD) patients, and the interaction effect between MBPS and dipping status for target organ damage (TOD). A total of 823 non-dialysis CKD patients were enrolled in this cross-sectional study. Subjects were grouped according to their systolic BP morning surge and dipping status, assessed by 24-hour ambulatory BP monitoring. Patients with elevated MBPS had the highest quartile of MBPS (≥26.89 mm Hg). Non-dipping pattern was defined as a decline in the nocturnal systolic BP of <10%. The factorial-designed analysis of variance indicated that there was no statistically significant interaction effect for TOD between MBPS and dipping status (P > .05). There was a statistically significant association between MBPS and the non-dipping pattern (OR 0.17, 95% CI 0.12-0.25; OR 0.92, 95% CI 0.91-0.93). Multiple linear regression analyses showed that excessive MBPS is an independent risk factor for poor renal function, independent of a non-dipping pattern, and BP level, whereas the non-dipping pattern was an important risk factor for left ventricular hypertrophy. Special attention should be paid to synchronous control of MBPS and nocturnal BP in CKD patients in clinical practice.

Prognostic value of pulmonary hypertension in pre-dialysis chronic kidney disease patients.

BACKGROUND: Pulmonary hypertension is common in chronic kidney disease (CKD) patients. However, the prognostic value of pulmonary hypertension in Chinese predialytic CKD patients is rarely reported. We evaluated the relevant factors and prognostic value of pulmonary hypertension in CKD patients. METHODS: This retrospective cohort study enrolled 1092 predialytic patients from The Third Affiliated Hospital of Sun Yat-Sen University from May 1st, 2011, to December 31st, 2016. Data of interest were retrieved from electronic medical records. Pulmonary hypertension was defined as pulmonary arterial systolic pressure (PASP) ≥ 35 mmHg by echocardiology. All participants were followed from the date of the first echocardiography examination. The primary endpoints were all-cause mortality and cardiovascular mortality. The secondary endpoint was end-stage renal disease (ESRD) defined as starting renal replacement therapy. RESULTS: The prevalence of pulmonary hypertension was 15.9% in the study population. For CKD stage 1, 2, 3a, 3b, 4 and 5, the prevalence was 6.0%, 9.6%, 17.2%, 13.3%, 20.7% and 26.6%, respectively. Older age, lower left ventricular ejection fraction, anemia and higher pulse pressure were independently associated with pulmonary hypertension in CKD patients. In multivariate Cox regression analysis, pulmonary hypertension was the independent risk factor for cardiovascular mortality, but not of all-cause mortality and ESRD. CONCLUSIONS: Pulmonary hypertension is not rare in early CKD patients. Patients with older age, anemia, higher pulse pressure and compromised heart function were more likely to comorbid pulmonary hypertension. Pulmonary hypertension maybe a sign of worse cardiovascular outcome in CKD patients.

Masked morning hypertension correlated with target organ damage in non-dialysis patients with chronic kidney disease.

OBJECTIVE: To determine the prevalence of masked morning hypertension and investigate its role in target organ damage in nondialysis patients with chronic kidney disease. METHODS: A total of 1841 patients with chronic kidney disease admitted to our hospital were recruited. According to measurements of clinic blood pressure and ambulatory blood pressure, they were divided into four groups: normotension, white-coat hypertension, masked morning hypertension, and sustained hypertension. Multivariate logistic regression analyses were used to evaluate the association between masked morning hypertension and cardiovascular and renal parameters. RESULTS: Overall, 288 (15.6%) patients were diagnosed with masked morning hypertension. Patients with masked morning hypertension had a higher prevalence of left ventricular hypertrophy, abnormal carotid intima-media thickness, and impaired renal function when compared with normotensive patients, although lower than those with sustained hypertension. After adjustment for demographics and clinical characteristics, masked morning hypertension was related to cardiovascular damage and renal dysfunction compared with normotension. The odds ratio for left ventricular hypertrophy, abnormal carotid intima-media thickness and impaired renal function was 1.955 [95% confidence interval (CI), 1.247-3.065], 1.469 (95% CI: 1.011-2.133), and 1.819 (95% CI: 1.112-2.976), respectively. Masked morning hypertension correlated with target organ damage even when patients with a history of cardiovascular disease were excluded. CONCLUSION: The prevalence of masked morning hypertension in nondialysis chronic kidney disease patients was high, and masked morning hypertension was associated with target organ damage in chronic kidney disease patients.

Dysbiosis of gut microbiota in adult idiopathic membranous nephropathy with nephrotic syndrome.

BACKGROUND: Gut bacterial microbiota is altered in patients with chronic kidney disease (CKD) and those on dialysis. However, it is not yet clear what bacterial composition changes occur in patients with idiopathic nephrotic syndrome (INS). We present in this report the changes in gut bacterial microbiota in INS patients with membranous nephropathy. METHODS: A total of 158 individuals were recruited for this study. Of these, 80 patients had stage 3-5 CKD without nephrotic syndrome (CKD group), 48 patients had INS and pathological diagnosis of membranous nephropathy (INS group), and 30 were age- and sex-matched healthy controls (HC group). The gut microbiome composition was analyzed using a 16S ribosomal RNA gene-based sequencing protocol. RESULTS: The results indicate that the nephrotic syndrome patients had a significantly different alpha and beta diversity compared with the CKD group and HC group (P < 0.01). At the phylum level, the INS patients showed increased Fusobacteria and Proteobacteria but reduced Firmicutes when compared with the HC group. At the genus level, Megamonas, Megasphaera, Akkermansia, and the butyrate-producing bacteria Lachnospira, Roseburia, and Fusobacterium were more abundant in the HC group (LDA score > 3) than the CKD and INS group. Fecal organic acid analysis revealed significantly lower quantities of propionate acid and butyric acid in INS than the HC group (P < 0.05). Compared with the HC group, we found that Parabacteroides was increased in CKD and INS patients. In addition, Oscillospira and Ruminococcus were more abundant in CKD patients than in the other two groups (LDA score > 3). At the genus level, ten bacterial taxa were more prevalent in the HC group. Providencia and Myroides were more prevalent in INS patients. CONCLUSION: Our findings highlight that, INS patients had a significantly different alpha and beta diversity and decreased gut microbiota-derived short-chain fatty acids, such as butyrate. However, large-scale prospective studies should be performed to identify the cause and effect factors of these changes in the microbiota in INS patients.

A longitudinal analysis of the relationship between serum uric acid and residual renal function loss in peritoneal dialysis patients.

Background: Hyperuricemia occurs frequently in patients with continuous ambulatory peritoneal dialysis (CAPD). This study aimed to evaluate the impact of serum uric acid (UA) over time on residual renal function (RRF) loss in a cohort of patients with CAPD.Methods: A total of 201 patients who started CAPD therapy between January 1, 2008 and April 30, 2016 were included in this single-center, retrospective cohort study. All patients were followed up until December 31, 2016. The median follow-up time was 23.43 ± 16.60 months. RRF loss was represented as the time to anuria.Results: Eighty-six patients developed anuria within 5 years. Multivariate Cox regression analysis showed that time-averaged serum UA and peritonitis were independent risk factors for RRF loss, while weekly Kt/V urea was a protective factor. Cox proportional hazard regression models showed that both patients with time-averaged uric acid (TA-UA) < 6.77 mg/dL [hazard ratio (HR) = 1.165, 95% confidence interval (CI) 1.054-1.387; p < 0.05] and those with TA-UA≥ 7.64 mg/dL (HR = 1.184, 95% CI 1.045-2.114; p < 0.05) had a higher risk of RRF than those with TA-UA in the range of 6.77-7.64 mg/dL. Penalized spline smoothing also showed a U-shaped relationship between continuous UA and RRF loss.Conclusion: The present study demonstrated that both high and low serum UA over time were associated with RRF loss in patients with CAPD.

The influence of cardiac valvular calcification on all-cause and cardiovascular mortality in maintenance hemodialysis patients.

OBJECTIVE: To investigate the effect of cardiac valve calcification (CVC) on all-cause and cardiovascular mortality in maintenance hemodialysis (MHD) patients. METHODS: A retrospective cohort study was conducted in 183 long-term hemodialysis patients with complete follow-up data from January 1, 2012, to December 30, 2015. The baseline data between CVC and non-CVC groups were compared. Kaplan-Meier method was used to analyze all-cause and cardiovascular mortality. The effect of CVC on prognosis was analyzed using the Cox proportional hazard regression model and subgroup analysis. RESULTS: Among 183 patients under hemodialysis, 104 (56.8%) were males, with an average age of 56.1 ± 17.0 years and 68 (37.2%) were complicated with valvular calcification. The median follow-up period was 30.8 months. All-cause and cardiovascular mortality were 50% vs. 14.8% and 25% vs. 7.0% in the CVC and non-CVC groups, respectively (P < 0.05). Kaplan-Meier indicated that differences in all-cause and cardiovascular mortality were statistically significant between the two groups (P < 0.001). Cox regression analysis showed that CVC significantly increased all-cause (hazards ratio [HR] 2.161 [1.083-4.315]) and cardiovascular mortality (3.435 [1.222-9.651]) after adjusting for multiple factors. Meanwhile, CVC also increases the incidence of new-onset cardiovascular events. Subgroup analysis revealed that all-cause and cardiovascular mortality were significantly higher in patients with aortic valve calcification (AVC) than in patients with mitral valve calcification (MVC). Multivariate calibration showed that AVC increased the risk of cardiovascular death (HR 5.486 [1.802-16.702]) (P < 0.05), whereas MVC did not. By further comparing the echocardiographic data of the two groups, the incidence of LVH and pulmonary hypertension in the AVC group was significantly higher than that in the MVC group. CONCLUSION: Valve calcification increases the risk of all-cause and cardiovascular mortality in MHD patients, also new-onset cardiovascular events, and aortic valve calcification contributes more to the risk of cardiovascular mortality.

Low serum uric acid levels increase the risk of all-cause death and cardiovascular death in hemodialysis patients.

BACKGROUND: Elevated serum uric acid (SUA) is associated with increased cardiovascular (CV) and all-cause mortality risk in the general population, but the impact of UA on mortality in hemodialysis patients is still controversial. The aim of the study was to explore the relationship between SUA and all-cause mortality and CV mortality in hemodialysis patients. METHODS: This retrospective, observational cohort study included 210 HD patients with a mean age of 56.6 ± 16.6 years. All demographic and laboratory data were recorded at baseline. The Kaplan-Meier method and Cox proportional hazard regression model were used to examine the association between SUA and all-cause mortality and CV mortality in HD patients. RESULTS: With 420 µmol/L (20th percentile) and 644 µmol/L (80th percentile) as the boundary points, the patients were divided into three groups. After a median follow-up of 49.8 months, 68 (32.4%) all-cause deaths and 34 (16.2%) CV deaths were recorded. The Kaplan-Meier method showed that with a decrease in SUA, all-cause mortality (log rank χ2 = 15.61, p = .000), and CV mortality (log rank χ2=14.28, p = .000) increased. Each 100 µmol/L increase in SUA was associated with lower all-cause mortality with an hazard ratio (HR) of 0.792 (0.645-0.972) and lower CV mortality with an HR of 0.683 (0.505-0.924) after adjusting for age, sex, and complications. Compared to the lowest quartile, all-cause mortality [HR 0.351(0.132-0.934), p = .036] and CV mortality [HR 0.112 (0.014-0.925), p = .042] were lower in the highest SUA quartile. CONCLUSION: A lower SUA level in HD patients was associated with a higher risk of all-cause mortality and CV mortality. Moreover, higher SUA concentrations may be cardioprotective in HD patients.

Sirt3 modulates fatty acid oxidation and attenuates cisplatin-induced AKI in mice.

Fatty acid oxidation (FAO) dysfunction is one of the important mechanisms of renal fibrosis. Sirtuin 3 (Sirt3) has been confirmed to alleviate acute kidney injury (AKI) by improving mitochondrial function and participate in the regulation of FAO in other disease models. However, it is not clear whether Sirt3 is involved in regulating FAO to improve the prognosis of AKI induced by cisplatin. Here, using a murine model of cisplatin-induced AKI, we revealed that there were significantly FAO dysfunction and extensive lipid deposition in the mice with AKI. Metabolomics analysis suggested reprogrammed energy metabolism and decreased ATP production. In addition, fatty acid deposition can increase reactive oxygen species (ROS) production and induce apoptosis. Our data suggested that Sirt3 deletion aggravated FAO dysfunction, resulting in increased apoptosis of kidney tissues and aggravated renal injury. The activation of Sirt3 by honokiol could improve FAO and renal function and reduced fatty acid deposition in wide-type mice, but not Sirt3-defective mice. We concluded that Sirt3 may regulate FAO by deacetylating liver kinase B1 and activating AMP-activated protein kinase. Also, the activation of Sirt3 by honokiol increased ATP production as well as reduced ROS and lipid peroxidation through improving mitochondrial function. Collectively, these results provide new evidence that Sirt3 is protective against AKI. Enhancing Sirt3 to improve FAO may be a potential strategy to prevent kidney injury in the future.

Abnormal circadian rhythm of urinary sodium excretion correlates closely with hypertension and target organ damage in Chinese patients with CKD.

Whether the abnormal circadian rhythm of urinary sodium excretion is associated with hypertension in chronic kidney disease (CKD) is poorly understood. In this study, we assessed the relationship between the circadian rhythm of urinary sodium excretion and hypertension. Urinary samples were collected during both the day (07:00 to 22:00) and night (22:00 to 07:00) to estimate night/day urinary sodium excretion ratios. Blood pressure (BP) and clinical data were also measured. A total of 1,099 Chinese CKD patients were recruited, 308 patients were excluded, and 791 patients were final enrolled in this study. Among them, 291 patients were normotensive and 500 were hypertensive CKD patients. A 1:1 propensity score matching (PSM) analysis was performed with age and estimated glomerular filtration rate (eGFR) matched between 190 normotensive and hypertensive patients. In the full cohort and PSM cohort, multivariate regression analysis showed that the night/day urinary sodium excretion ratio was an independent risk factor for clinical hypertension, whereas 24 h urinary sodium excretion, diurnal and nocturnal urinary sodium excretion were not. When the night/day urinary sodium excretion ratios were further divided into tertiles (tertile 1 < 0.47, tertile 2, 0.47-0.84 and tertile 3 > 0.84), multivariate analysis showed that tertile 3 was independently associated with hypertension in the full and PSM cohorts. In addition, tertile 3 was also independently associated with eGFR ≤ 60 mL/min/1.73 m2 and left ventricular hypertrophy. These data suggested that an abnormal circadian rhythm of urinary sodium excretion was independently associated with hypertension and target-organ damage. Individualized salt intake and therapeutic strategies should be used to normalize the natriuretic dipping profile in CKD patients.

Circular RNA expression profiles in cisplatin-induced acute kidney injury in mice.

Aim: This study was carried out to identify the expression profile and role of circRNAs in cisplatin-induced acute kidney injury (AKI). Materials & methods: In this study, an AKI model was established in cisplatin-treated mice, and the expression of circRNAs was profiled by next-generation sequencing. The differential expression levels of selected circRNAs were determined by quantitative real-time polymerase chain reaction. Bioinformatics analysis was conducted to predict the functions. Results: In total, 368 circRNAs were detected to be differentially expressed in response to cisplatin treatment. Bioinformatics analysis indicated that the parental genes of the differentially expressed circRNAs were predominantly implicated in the cell and cell part, cellular process and cancer pathways. Conclusion: CircRNAs might be differentially expressed in AKI, which are potentially involved in pathophysiology of cisplatin-induced nephrotoxicity.

Inhibition of hyperglycolysis in mesothelial cells prevents peritoneal fibrosis.

Progressive peritoneal fibrosis affects patients receiving peritoneal dialysis (PD) and has no reliable treatment. The mechanisms that initiate and sustain peritoneal fibrosis remain incompletely elucidated. To overcome these problems, we developed a strategy that prevents peritoneal fibrosis by suppressing PD-stimulated mesothelial-to-mesenchymal transition (MMT). We evaluated single-cell transcriptomes of mesothelial cells obtained from normal peritoneal biopsy and effluent from PD-treated patients. In cells undergoing MMT, we found cellular heterogeneity and intermediate transition states associated with up-regulation of enzymes involved in glycolysis. The expression of glycolytic enzymes was correlated with the development of MMT. Using gene expression profiling and metabolomics analyses, we confirmed that PD fluid induces metabolic reprogramming, characterized as hyperglycolysis, in mouse peritoneum. We found that transforming growth factor ß1 (TGF-ß1) can substitute for PD fluid to stimulate hyperglycolysis, suppressing mitochondrial respiration in mesothelial cells. Blockade of hyperglycolysis with 2-deoxyglucose (2-DG) inhibited TGF-ß1-induced profibrotic cellular phenotype and peritoneal fibrosis in mice. We developed a triad of adeno-associated viruses that overexpressed microRNA-26a and microRNA-200a while inhibiting microRNA-21a to target hyperglycolysis and fibrotic signaling. Intraperitoneal injection of the viral triad inhibited the development of peritoneal fibrosis induced by PD fluid in mice. We conclude that hyperglycolysis is responsible for MMT and peritoneal fibrogenesis, and this aberrant metabolic state can be corrected by modulating microRNAs in the peritoneum. These results could provide a therapeutic strategy to combat peritoneal fibrosis.

Nocturnal pulse rate correlated with ambulatory blood pressure and target organ damage in patients with chronic kidney disease.

The relationship between resting pulse rate (PR) and the occurrence of hypertension and cardiovascular (CV) mortality has been described in the general population. Few studies have examined the relationship between ambulatory PR, ambulatory blood pressure (BP), and target organ damage (TOD) in patients with chronic kidney disease (CKD). A total of 1509 patients with CKD were recruited in our hospital. Ambulatory blood pressure monitoring (ABPM) over a 24-hours period was performed and referenced with clinical data in this cross-sectional study. TOD was measured by estimated glomerular filtration rate (eGFR), left ventricular hypertrophy (LVH), and carotid intima-media thickness (cIMT). Univariate and multivariate analyses were used to evaluate the relationship between PR, BP, and TOD. The percentage of male patients was 58.3% with a mean age of 44.6 ± 16.2 years. Nocturnal PR rather than 24-hours PR or daytime PR was an independent risk factor for clinical hypertension, 24-hours hypertension, BP dipper state, poor renal function, and LVH. In addition, the authors found that nighttime PR >74 beats/min (bpm) group was independently associated with clinical hypertension, 24-hours hypertension, day and night hypertension, nondipping BP, lower eGFR, and LVH when compared with nighttime PR <64 bpm group. Furthermore, 1:1 propensity score matching between PR ≤74 bpm group and PR >74 bpm group was performed. Multivariate analyses indicated nighttime PR >74 bpm remained independently associated with clinical hypertension, daytime and nighttime hypertension, and LVH. An increased nocturnal PR is associated with TOD, higher BP, and nondipping BP in patients with CKD.