Hypokalemia, Kidney Function, and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is an increasing health problem associated with high morbidity and mortality rates. Several reports have shown an association between hypokalemia and clinical outcomes in patients with heart failure (HF). However, the association of hypokalemia with kidney function and clinical outcomes in patients with HFpEF remains unclear.Methods and Results: We measured serum potassium levels and kidney function in 454 patients with HFpEF (mean age 76 years; 55% men) at admission. Hypokalemia (K+<3.5 mmol/L) and hyperkalemia (K+>5.0 mmol/L) were identified in 58 (12.7%) and 11 (2.4%) patients, respectively. Patients with hypokalemia showed renal tubular damage (RTD), defined as a urinary ß2-microglobulin to creatinine ratio ≥300 µg/gCr, preserved estimated glomerular filtration rate (eGFR), and plasma volume expansion. Multivariate logistic analysis demonstrated that RTD, preserved eGFR, and plasma volume expansion were significantly associated with hypokalemia. During the median follow-up period of 1,000 days, 82 HF-related events occurred. Kaplan-Meier analysis showed that patients with hypokalemia had a higher rate of HF-related events than those without hypokalemia. Multivariate Cox proportional hazard regression analysis demonstrated that hypokalemia was significantly associated with HF-related events after adjusting for confounding factors. CONCLUSIONS: Hypokalemia is affected by kidney function, notably RTD, in patients with HFpEF. Hypokalemia is a risk factor for HF-related events in patients with HFpEF.

Renal tubular damage and clinical outcome in heart failure with preserved ejection fraction and chronic kidney disease.

AIMS: Despite advances in heart failure (HF) treatment, HF with preserved ejection fraction (HFpEF) remains a health problem with a high mortality rate. HFpEF is composed of diverse phenogroups, of which patients with concomitant renal impairment have worse outcomes. Renal tubular damage (RTD) is associated with the development of HF and chronic kidney disease (CKD). However, the impact of RTD on HF progression in patients with HFpEF and CKD remains unclear. The aim of the present study was to examine whether RTD could predict HF-related events in patients with HFpEF and CKD. METHODS AND RESULTS: We measured RTD markers, such as urinary ß2 -microglobulin to creatinine ratio (UBCR) and N-acetyl-ß-d-glucosamidase (NAG) level, in 319 consecutive patients with HFpEF and CKD who were hospitalized for acute HF (49% females, mean age 76 ± 12). Based on previous reports, high UBCR and high NAG levels were defined as UBCR ≥300 µg/gCr and NAG >14.2 U/gCr, respectively. There were 91 HF-related events, defined as HF hospitalizations or HF deaths, during the median follow-up period of 5.2 years. The prevalence of high UBCR increased with advancing New York Heart Association functional class and albuminuria. Kaplan-Meier analysis demonstrated that patients with high UBCR had more HF-related events than those with normal or low UBCR. Multivariate Cox proportional hazards regression analyses demonstrated that high UBCR, but not high NAG level, was an independent predictor of HF-related events after adjusting for confounding risk factors in patients with HFpEF and CKD (hazard ratio, 2.60; 95% confidence interval, 1.52-4.72; P = 0.0009). UBCR significantly improved the C-statistic, with a significant net reclassification index and integrated discrimination improvement (0.738 vs. 0.684; P = 0.0244). CONCLUSION: RTD, as assessed by a high UBCR, was associated with the severity and clinical outcomes of HFpEF and CKD, indicating that it could be a feasible marker for HF progression.

Normal values for pediatric urinary biochemistry in early infancy.

BACKGROUND: Urinary levels of N-acetyl-ß-D-glucosaminidase (NAG), α1-microglobulin (α1-MG), and ß2-microglobulin (ß2-MG) are measured as markers of renal tubular damage. We previously determined normal values for these urine biochemical examinations in healthy children over 3 years old. However, the values are not applicable to children younger than 2 years old, and children less than 1 year old, in particular, seem to show very high levels for all these markers. Hence, as normal values for children below 2 years old remain unclear, we determined the normal values for urinary biochemical markers in this age group. MATERIAL AND METHODS: Fresh urine samples were obtained from 293 healthy children (from newborns to 2-year-old children). All the samples were subjected to normal urinalysis. NAG, α1-MG, ß2-MG, and creatinine (Cr) levels in extracted samples were measured immediately in the central laboratory at Kanazawa Medical Center. RESULTS: The normal values for each biomarker in children below 2 years of age were determined. Additionally, urinary α1-MG levels were observed to decrease most rapidly with age, almost reaching the level at ≥ 3 years by 6 months after birth. CONCLUSION: Renal tubular function can be evaluated in children < 3 years old using the normal values. Further, the most stable and useful urinary marker from early infancy seems to be urinary α1-MG.

Coexposure to multiple metals and renal tubular damage: a population-based cross-sectional study in China's rural regions.

Previous studies have indicated that exposure to a single toxic metal can cause renal tubular damage, while evidence about the effects of multimetal exposure on renal tubular damage is relatively limited. We aimed to evaluate the relationships of multimetal coexposure with renal tubular damage in adults in heavy metal-polluted rural regions of China. A cross-sectional study of 1918 adults in China's heavy metal-contaminated rural regions was conducted. Inductively coupled plasma-mass spectrometry (ICP-MS) was used to measure the plasma levels of 18 metals in participants, and immune turbidimetry was used to measure sensitive biological indicators, reflecting renal tubular damage (including retinol-binding protein and ß2-microglobulin). Least absolute shrinkage and selection operator (LASSO) penalized regression analysis, logistic and linear regression analysis, restricted cubic spline (RCS) regression analysis and the Bayesian kernel machine regression (BKMR) method were used to explore associations of multimetal coexposure with renal tubular damage risk or renal tubular damage indicators. Plasma selenium, cadmium, arsenic, and iron were identified as the main plasma metals associated with renal tubular damage risk after dimensionality reduction. Multimetal regression models showed that selenium was positively associated, and iron was negatively associated with renal tubular damage risk or its biological indicators. Multimetal RCS analyses additionally revealed a non-linear relationship of selenium with renal tubular damage risk. The BKMR models showed that the metal mixtures were positively associated with biological indicators of renal tubular damage when the metal mixtures were above the 50th percentile of concentration. Our findings indicated that natural exposure to high levels of multimetal mixtures increases the risk of renal tubular damage. Under the conditions of multimetal exposure, selenium was positively associated, and iron was negatively associated with renal tubular damage risk or its biological indicators.

Polyunsaturated fatty acids ameliorate renal stone-induced renal tubular damage via miR-93-5p/Pknox1 axis.

OBJECTIVES: Polyunsaturated fatty acids (PUFAs) can decrease the risk of calcium oxalate stone formation, which accounts for 80% of all renal stones. This study aimed to investigate the protective mechanisms of PUFAs against renal stones. METHODS: Urine samples of patients with renal stones and biopsy tissue samples from patients with nephrocalcinosis were tested for miR-93-5p expression. A renal stone mouse model was established with intraperitoneal injection of glyoxylic acid, during which mice were treated with PUFAs and/or an miR-93-5p inhibitor adenovirus. Periodic acid-Schiff staining, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling staining, oil red O staining, triacylglycerol assay, and colorimetry testing were performed to assess glycogen deposition, apoptosis, lipid accumulation, blood urea nitrogen, and serum creatinine levels, respectively. Renal proximal tubular epithelial cells (human kidney 2 [HK-2]) were subjected to gain- and loss-of-function assays before calcium-oxalate monohydrate (COM) induction and PUFA treatment. Cell counting kit 8, flow cytometry, and lactate dehydrogenase activity assays were used to examine cell viability, apoptosis, and damage. A luciferase reporter gene assay verified the interaction between miR-93-5p and Pknox1, and miR-93-5p and Pknox1 levels were assessed using a reverse transcription-quantitative polymerase chain reaction and Western blot analysis. RESULTS: miR-93-5p was downregulated in clinical samples with renal stones and negatively targeted Pknox1. PUFAs increased miR-93-5p expression and reduced apoptosis, glycogen deposition, and lipid accumulation in mice with renal stones, which were annulled by miR-93-5p downregulation. PUFAs increased proliferation and diminished apoptosis, lipid accumulation, and lactate dehydrogenase activity in COM-induced HK-2 cells, which were negated by miR-93-5p inhibition. Pknox1 overexpression reversed the effect of miR-93-5p upregulation on COM-induced HK-2 cells. CONCLUSIONS: PUFAs repressed renal stone-induced renal tubular damage via the miR-93-5p/Pknox1 axis.

Galectin-3, Acute Kidney Injury and Myocardial Damage in Patients With Acute Heart Failure.

BACKGROUND: Galectin-3, a biomarker of inflammation and fibrosis, can be associated with renal and myocardial damage and dysfunction in patients with acute heart failure (AHF). METHODS AND RESULTS: We retrospectively analyzed 790 patients with AHF who were enrolled in the AKINESIS study. During hospitalization, patients with galectin-3 elevation (> 25.9 ng/mL) on admission more commonly had acute kidney injury (assessed by KDIGO criteria), renal tubular damage (peak urine neutrophil gelatinase-associated lipocalin [uNGAL] > 150 ng/dL) and myocardial injury (≥ 20% increase in the peak high-sensitivity cardiac troponin I [hs-cTnI] values compared to admission). They less commonly had ≥ 30% reduction in B-type natriuretic peptide from admission to last measured value. In multivariable linear regression analysis, galectin-3 was negatively associated with estimated glomerular filtration rate and positively associated with uNGAL and hs-cTnI. Higher galectin-3 was associated with renal replacement therapy, inotrope use and mortality during hospitalization. In univariable Cox regression analysis, higher galectin-3 was associated with increased risk for the composite of death or rehospitalization due to HF and death alone at 1 year. After multivariable adjustment, higher galectin-3 levels were associated only with death. CONCLUSIONS: In patients with AHF, higher galectin-3 values were associated with renal dysfunction, renal tubular damage and myocardial injury, and they predicted worse outcomes.

Decongestion, kidney injury and prognosis in patients with acute heart failure.

BACKGROUND: In patients with acute heart failure (AHF), the development of worsening renal function with appropriate decongestion is thought to be a benign functional change and not associated with poor prognosis. We investigated whether the benefit of decongestion outweighs the risk of concurrent kidney tubular damage and leads to better outcomes. METHODS: We retrospectively analyzed data from the AKINESIS study, which enrolled AHF patients requiring intravenous diuretic therapy. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and B-type natriuretic peptide (BNP) were serially measured during the hospitalization. Decongestion was defined as ≥30% BNP decrease at discharge compared to admission. Univariable and multivariable Cox models were assessed for one-year mortality. RESULTS: Among 736 patients, 53% had ≥30% BNP decrease at discharge. Levels of uNGAL and BNP at each collection time point had positive but weak correlations (r ≤ 0.133). Patients without decongestion and with higher discharge uNGAL values had worse one-year mortality, while those with decongestion had better outcomes regardless of uNGAL values (p for interaction 0.018). This interaction was also significant when the change in BNP was analyzed as a continuous variable (p < 0.001). Although higher peak and discharge uNGAL were associated with mortality in univariable analysis, only ≥30% BNP decrease was a significant predictor after multivariable adjustment. CONCLUSIONS: Among AHF patients treated with diuretic therapy, decongestion was generally not associated with kidney tubular damage assessed by uNGAL. Kidney tubular damage with adequate decongestion does not impact outcomes; however, kidney injury without adequate decongestion is associated with a worse prognosis.

In Vivo and In Vitro Evaluation of Urinary Biomarkers in Ischemia/Reperfusion-Induced Kidney Injury.

Oxidative stress plays an important role in the pathophysiology of acute kidney injury (AKI). Previously, we reported that vanin-1, which is involved in oxidative stress, is associated with renal tubular injury. This study was aimed to determine whether urinary vanin-1 is a biomarker for the early diagnosis of AKI in two experimental models: in vivo and in vitro. In a rat model of AKI, ischemic AKI was induced in uninephrectomized rats by clamping the left renal artery for 45 min and then reperfusing the kidney. On Day 1 after renal ischemia/reperfusion (I/R), serum creatinine (SCr) in I/R rats was higher than in sham-operated rats, but this did not reach significance. Urinary N-acetyl-ß-D-glucosaminidase (NAG) exhibited a significant increase but decreased on Day 2 in I/R rats. In contrast, urinary vanin-1 significantly increased on Day 1 and remained at a significant high level on Day 2 in I/R rats. Renal vanin-1 protein decreased on Days 1 and 3. In line with these findings, immunofluorescence staining demonstrated that vanin-1 was attenuated in the renal proximal tubules of I/R rats. Our in vitro results confirmed that the supernatant from HK-2 cells under hypoxia/reoxygenation included significantly higher levels of vanin-1 as well as KIM-1 and NGAL. In conclusion, our results suggest that urinary vanin-1 might be a potential novel biomarker of AKI induced by I/R.

Renal Involvement in Children with Type 2 Diabetes Mellitus Onset: A Pilot Study.

Type 2 Diabetes Mellitus (T2DM) is a main cause of chronic kidney disease (CKD) in adulthood. No studies have examined the occurrence of acute kidney injury (AKI)-that enhances the risk of later CKD-and renal tubular damage (RTD)-that can evolve to AKI-in children with onset of T2DM. We aimed to evaluate the prevalence and possible features of AKI and RTD in a prospectively enrolled population of children with onset of T2DM. We consecutively enrolled 10 children aged 12.9 ± 2.3 years with newly diagnosed T2DM. AKI was defined according to the KDIGO criteria. RTD was defined by abnormal urinary beta-2-microglobulin and/or tubular reabsorption of phosphate (TRP) <85% and/or fractional excretion of Na >2%. None of the patients developed AKI, whereas 3/10 developed RTD with high beta-2-microglobulin levels (range: 0.6-1.06 mg/L). One of these three patients also presented with reduced TRP levels (TRP = 70%). Proteinuria was observed in two out of three patients with RTD, while none of patients without RTD had proteinuria. Patients with RTD presented higher beta-2-microglobulin, acute creatinine/estimated basal creatinine ratio, and serum ketones levels compared with patients without RTD. In conclusion, in our pilot observation, we found that none of the 10 children with T2DM onset developed AKI, whereas three of them developed RTD.

Is Urinary Netrin-1 a Good Marker of Tubular Damage in Preterm Newborns?

There is a lack of a good marker for early kidney injury in premature newborns. In recent publications, netrin-1 seems to be a promising biomarker of kidney damage in different pathological states. The study aimed to measure the urinary level of netrin-1 depending on gestational age. A prospective study involved 88 newborns (I-60 premature newborns, II-28 healthy term newborns). Additionally, premature babies were divided for 2 groups: IA-28 babies born between 30-34 weeks of gestation and IB-32 born at 35-36 weeks. The median urinary concentration of netrin-1 was: IA-(median, Q1-Q3) 63.65 (56.57-79.92) pg/dL, IB-61.90 (58.84-67.17) pg/dL, and II-60.37 (53.77-68.75) pg/dL, respectively. However urinary netrin-1 normalized by urinary concentration of creatinine were IA-547.9 (360.2-687.5) ng/mg cr., IB-163.64 (119.15-295.96) ng/mg cr., and II-81.37 (56.84-138.58) ng/mg cr., respectively and differ significantly between the examined groups (p = 0.00). The netrin-1/creatinine ratio is increased in premature babies. Further studies examining the potential factors influencing kidney function are necessary to confirm its potential value in the diagnosis of subclinical kidney damage in premature newborns.

TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage.

Indoxyl sulfate (IS) is accumulated during severe renal insufficiency and known for its nephrotoxic properties. Transient receptor potential vanilloid 1 (TRPV1) is present in the kidney and acts as a renal sensor. However, the mechanism underlying IS-mediated renal tubular damage in view of TRPV1 is lacking. Here, we demonstrated that TRPV1 was expressed in tubular cells of Lilly Laboratories cell-porcine kidney 1 (LLC-PK1) and Madin-Darby canine kidney cells (MDCK). IS treatment in both cells exhibited tubular damage with increased LDH release and reduced cell viability in dose- and time-dependent manners. MDCK, however, was more vulnerable to IS. We, therefore, investigated MDCK cells to explore a more detailed mechanism. Interestingly, IS-induced tubular damage was markedly attenuated in the presence of selective TRPV1 blockers. IS showed no effect on TRPV1 expression but significantly increased arachidonate 12-lipoxygenase (ALOX12) protein, mRNA expression, and 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) amounts in a dose-dependent manner, indicating that the ALOX12/12(S)-HETE pathway induced TRPV1 hyperfunction in IS-mediated tubulotoxicity. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy-α-cyanocinnamate or baicalein attenuated the effects of IS. Since aryl hydrocarbon receptor (AhR) activation after IS binding is crucial in mediating cell death, here, we found that the AhR blockade not only ameliorated tubular damage but also attenuated ALOX12 expression and 12(S)-HETE production caused by IS. The uremic toxic adsorbent AST-120, however, showed little effect on ALOX12 and 12(S)-HETE, as well as IS-induced cell damage. These results clearly indicated that IS activated AhR and then upregulated ALOX12, and this induced endovanilloid 12(S)-HETE synthesis and contributed to TRPV1 hyperfunction in IS-treated tubular cells. Further study on TRPV1 may attenuate kidney susceptibility to the functional loss of end-stage kidney disease via IS.

High ACR level is a strong risk factor for renal tubular impairment in patients with type 2 diabetes: A longitudinal observational study.

BACKGROUND: Several studies have indicated that high albuminuria is associated with renal function decline. However, the relationship between the urinary albumin-to-creatinine ratio (ACR) and risk of developing tubular injury remains unclear. Our aim was to investigate the association of ACR with the risk of developing tubular impairment in patients with type 2 diabetes. METHODS: This longitudinal observational study compared baseline with follow-up data in 183 patients with type 2 diabetes. ACR, urinary alpha-1-microglobulin-to-creatinine ratio (A1MCR) and estimated glomerular filtration rate (eGFR) were used to evaluate albuminuira, tubular injury and glomerular filtration function, respectively. RESULTS: Levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and A1MCR were significantly different at the two-year follow-up compared with baseline levels. Among patients both with baseline ACR above and below 30 mg/g, the percentage with A1MCR > 15 mg/g clearly increased after follow-up (P < 0.05). The risk of A1MCR rising from normal ranges to >15 mg/g over the follow-up increased with increasing baseline ACR values lower baseline eGFR. Among the patients with baseline ACR > 63.10 mg/g, all showed increased A1MCR values at follow-up compared with baseline. In the multivariate regression analysis, the patients with baseline ACR > 63.10 mg/g had a strong risk of A1MCR rising from normal to >15 mg/g (odds ratio (OR) = 11.12, P = 0.001) over the follow-up, while the males had a 2.89-fold risk of A1MCR increasing from normal to >15 mg/g compared with females. CONCLUSION: Baseline ACR level is related to increased risk of developing renal tubular injury; in particular, this association is much stronger in patients with type 2 diabetes and baseline ACR > 63.10 mg/g.

Interleukin-36α as a potential biomarker for renal tubular damage induced by dietary phosphate load.

Excessive intake of phosphate has been known to induce renal tubular damage and interstitial inflammation, leading to acute kidney injury or chronic kidney disease in rodents and humans. However, sensitive and early biomarkers for phosphate-induced kidney damage remain to be identified. Our previous RNA sequencing analysis of renal gene expression identified interleukin-36α (IL-36α) as a gene significantly upregulated by dietary phosphate load in mice. To determine the time course and dose dependency of renal IL-36α expression induced by dietary phosphate load, we placed mice with or without uninephrectomy on a diet containing either 0.35%, 1.0%, 1.5%, or 2.0% inorganic phosphate for 10 days, 4 weeks, or 8 weeks and evaluated renal expression of IL-36α and other markers of tubular damage and inflammation by quantitative RT-PCR, immunoblot analysis, and immunohistochemistry. We found that IL-36α expression was induced in distal convoluted tubules and correlated with phosphate excretion per nephron. The increase in IL-36α expression was simultaneous with but more robust in amplitude than the increase in tubular damage markers such as Osteopontin and neutrophil gelatinase-associated lipocalin, preceding the increase in expression of other inflammatory cytokines, including transforming growth factor-α, interleukin-1ß, and transforming growth factor-ß1. We conclude that IL-36α serves as a marker that reflects the degree of phosphate load excreted per nephron and of associated kidney damage.

Expression and pathophysiological significance of carbohydrate response element binding protein (ChREBP) in the renal tubules of diabetic kidney.

Carbohydrate response element binding protein (ChREBP), a glucose responsive transcription factor, mainly regulates expression of genes involved in glucose metabolism and lipogenesis. Recently, ChREBP is speculated to be involved in the onset and progression of diabetic nephropathy (DN). However, there exists no report regarding the localization and function of ChREBP in the kidney. Therefore, we analyzed the localization of Chrebp mRNA expression in the wild type (WT) mice kidney using laser microdissection method, and observed its dominant expression in the proximal tubules. In diabetic mice, mRNA expression of Chrebp target genes in the proximal tubules, including Chrebpß and thioredoxin-interacting protein (Txnip), significantly increased comparing with that of WT mice. Co-overexpression of ChREBP and its partner Mlx, in the absence of glucose, also increased TXNIP mRNA expression as well as high glucose in human proximal tubular epithelial cell line HK-2. Since TXNIP is well known to be involved in the production of reactive oxygen species (ROS), we next examined the effect of ChREBP/Mlx co-overexpression, in the absence of glucose, on ROS production in HK-2 cells. Interestingly, ChREBP/Mlx co-overexpression also induced ROS production significantly as well as high glucose. Moreover, both high glucose-induced increase of TXNIP mRNA expression and ROS production were abrogated by ChREBP small interfering RNA transfection. Taken together, high glucose-activated ChREBP in the renal proximal tubules induce the expression of TXNIP mRNA, resulting in the production of ROS which may cause renal tubular damage. It is therefore speculated that ChREBP is involved in the onset and progression of DN.

Involvement of Vanin-1 in Ameliorating Effect of Oxidative Renal Tubular Injury in Dahl-Salt Sensitive Rats.

In salt-sensitive hypertension, reactive oxygen species (ROS) play a major role in the progression of renal disease partly through the activation of the mineralocorticoid receptor (MR). We have previously demonstrated that urinary vanin-1 is an early biomarker of oxidative renal tubular injury. However, it remains unknown whether urinary vanin-1 might reflect the treatment effect. The objective of this study was to clarify the treatment effect for renal tubular damage in Dahl salt-sensitive (DS) rats. DS rats (six weeks old) were given one of the following for four weeks: high-salt diet (8% NaCl), high-salt diet plus a superoxide dismutase mimetic, tempol (3 mmol/L in drinking water), high-salt diet plus eplerenone (100 mg/kg/day), and normal-salt diet (0.3% NaCl). After four-week treatment, blood pressure was measured and kidney tissues were evaluated. ROS were assessed by measurements of malondialdehyde and by immunostaining for 4-hydroxy-2-nonenal. A high-salt intake for four weeks caused ROS and histological renal tubular damages in DS rats, both of which were suppressed by tempol and eplerenone. Proteinuria and urinary N-acetyl-ß-D-glucosaminidase exhibited a significant decrease in DS rats receiving a high-salt diet plus eplerenone, but not tempol. In contrast, urinary vanin-1 significantly decreased in DS rats receiving a high-salt diet plus eplerenone as well as tempol. Consistent with these findings, immunohistochemical analysis revealed that vanin-1 was localized in the renal proximal tubules but not the glomeruli in DS rats receiving a high-salt diet, with the strength attenuated by tempol or eplerenone treatment. In conclusion, these results suggest that urinary vanin-1 is a potentially sensitive biomarker for ameliorating renal tubular damage in salt-sensitive hypertension.

Vanin-1 in Renal Pelvic Urine Reflects Kidney Injury in a Rat Model of Hydronephrosis.

Urinary tract obstruction and the subsequent development of hydronephrosis can cause kidney injuries, which results in chronic kidney disease. Although it is important to detect kidney injuries at an early stage, new biomarkers of hydronephrosis have not been identified. In this study, we examined whether vanin-1 could be a potential biomarker for hydronephrosis. Male Sprague-Dawley rats were subjected to unilateral ureteral obstruction (UUO). On day 7 after UUO, when the histopathological renal tubular injuries became obvious, the vanin-1 level in the renal pelvic urine was significantly higher than that in voided urine from sham-operated rats. Furthermore, vanin-1 remained at the same level until day 14. There was no significant difference in the serum vanin-1 level between sham-operated rats and rats with UUO. In the kidney tissue, the mRNA and protein expressions of vanin-1 significantly decreased, whereas there was increased expression of transforming growth factor (TGF)-ß1 and Snail-1, which plays a pivotal role in the pathogenesis of renal fibrosis via epithelial-to-mesenchymal transition (EMT). These results suggest that vanin-1 in the renal pelvic urine is released from the renal tubular cells of UUO rats and reflects renal tubular injuries at an early stage. Urinary vanin-1 may serve as a candidate biomarker of renal tubular injury due to hydronephrosis.

Long-term renal tubular damage in intrauterine growth-restricted rats.

BACKGROUND: Intrauterine growth restriction (IUGR) has been shown to be associated with increased risk of renal disease or hypertension in later life. Glomerular dysfunction, however, has mainly been reported, and limited information is available to link IUGR with renal tubular damage. The aim of this study was therefore to investigate urinary markers of tubular damage in a rat model of IUGR induced by bilateral uterine artery ligation. METHODS: Pregnant Sprague-Dawley rats underwent bilateral uterine artery ligation, while the control group underwent sham surgery. RESULTS: Birthweight was reduced, and urinary ß2-microglobulin (ß2-MG)-, cystatin C (Cys-C)-, and calbindin-to-creatinine ratios were significantly higher at weeks 4 and 8 in the IUGR group compared with the control group. These urinary markers were not significantly different at week 16 between the two groups. Increased excretion of urinary ß2-MG, Cys-C, and calbindin was observed in IUGR rats at ≥8 weeks of age. CONCLUSION: Children born with IUGR are at increased risk for renal tubular damage.

Silencing of SOCS-1 and SOCS-3 suppresses renal interstitial fibrosis by alleviating renal tubular damage in a rat model of hydronephrosis.

Our study was performed to elucidate how SOCS-1/3 silencing suppresses renal interstitial fibrosis (RIF) by alleviating renal tubular damage in rat models affected by hydronephrosis. Male Wistar rats were randomly selected to establish hydronephrosis rat model, after which all rats were classified into normal, model, negative control (NC), siRNA-SOCS-1, siRNA-SOCS-3, and siRNA-SOCS-1 + siRNA-SOCS-3 groups. The levels of urine protein, serum creatinine (Scr), and blood urea nitrogen (BUN) were detected. ELISA was performed to determine levels of cystatin (CysC), ß2-microglobulin (ß2-MG), interleukin (IL)-6, and tumor necrosis factor (TNF)-α. RT-qPCR and Western blotting were used for mRNA and protein expressions of SOCS-1, SOCS-3, α-smooth muscle actin (α-SMA), and transforming Growth Factor (TGF)-ß1. Compared with the normal group, the levels of Scr, BUN, urine protein, NAG, CysC, ß2-MG, IL-6, and TNF-α were increased in other groups, as well as elevated mRNA and protein expressions of SOCS-1, SOCS-3, α-SMA, and TGF-ß1. The siRNA-SOCS-1, siRNA-SOCS-3, and siRNA-SOCS-1 + siRNA-SOCS-3 groups were found with decreased levels of Scr, BUN, urine protein, NAG, CysC, ß2-MG, IL-6, and TNF-α, as well as mRNA and protein expressions of SOCS-1, SOCS-3, α-SMA, and TGF-ß1, including positive rates of SOCS-1 and SOCS-3 proteins in comparison with the model and NC groups. In comparison with the siRNA-SOCS-1 and siRNA-SOCS-3 groups, the siRNA-SOCS-1 + siRNA-SOCS-3 group exhibited decreased levels of Scr, BUN, urine protein, NAG, CysC, ß2-MG, IL-6, and TNF-α. Our study demonstrated that silencing of SOCS-1/3 may suppress RIF by alleviating the renal tubular damage in rat models affected by hydronephrosis.