Nephrin Levels Research Articles

Icariin improves acute kidney injury and proteinuria in a rat model of pregnancy‑induced hypertension.

Icariin has previously been demonstrated to attenuate hyperglycemia-induced renal injury, however the renoprotective effects of icariin in a rat model of pregnancy-induced hypertension (PIH) remain to be elucidated. The present study aimed to investigate the effect of icariin on PIH-induced acute kidney injury (AKI) and proteinuria. Following 18 days of icariin treatment between day 1 and day 18 of gestation, which was combined with NG-nitro-L-arginine methyl ester (L-NAME) treatment between day 12 and day 18 of gestation to induce PIH, the 24 h urine protein level, blood urea nitrogen and serum creatinine were measured by using the Coomassie Brilliant Blue method, a commercial enzymatic kit and the picric acid method, respectively. Renal tissues were collected at day 18 of gestation for hematoxylin and eosin staining and immunohistochemistry. The mRNA expression of AGT and protein expression of angiotensin II (Ang II) in the kidneys of control and PIH rats was investigated by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively, to determine the effect of icariin on components of the renin-angiotensin system. The results demonstrated that L-NAME treatment in pregnant rats resulted in significant increases in systolic blood pressure (SBP) and diastolic blood pressure, in addition to the induction of severe proteinuria. The significant increase in SBP and proteinuria in PIH rats was prevented by icariin. L-NAME-induced AKI resulted in profound renal histological alterations, including mesangial expansion and glomerular lesions. L-NAME administration exerted a marked decrease in the mRNA and protein expression levels of nephrin in the kidneys from PIH rats compared with control group. Furthermore, upregulation of circulating and renal Ang II levels in PIH rats was observed. However, icariin treatment significantly reversed the L-NAME-induced downregulation of nephrin and upregulation of circulating and renal Ang II levels in PIH rats. These results demonstrated that icariin administration improved urinary protein excretion levels and renal tissue damage in PIH rats, and the underlying mechanism was mediated in part, via upregulation of nephrin expression and downregulation of Ang II.

ASSESSMENT OF NEPHRIN AND PODOCIN LEVELS IN THE URINE OF PATIENTS WITH DIABETES MELLITUS

THE AIM:to assess excretion value of podocytes injury biomarkers in urine and to clarify their significance for early diabetic nephropathy (DN) diagnostics in diabetes mellitus (DM) patients with different severity of albuminuria (AU)/proteinuria(PU).PATIENTS AND METHODS.74 DM pts were studied, including 30 with type1 DM (T1DM) and 44 pts with type2 DM (T2DM). They were divided into three groups: 41 pts with AU <30 mg/gCr (A1), 13 pts with AU 30-300 mg/gCr (A2), 20 pts with PU (A3). CKD S1 was revealed in 41pts, CKD S2 – in 25 pts, CKD S3 – in 8 pts. Arterial hypertension was observed in 52 pts of 74(70%), mainly in T2DM. 10 healthy subjects were studied as control. Urinary levels of nephrin and podocin (an important slit diaphragm proteins) were measured by ELISA.RESULTS.Nephrinuria (NU) >5,84ng/ml/g, which not detecting in controls, was revealed in 63% of A1 pts, in 77% – in A2, in 80% – in A3. Podocinuria (PdU)>1,73ng/ml/g was revealed in 78% of A1 pts, in 54% of A2 and in 83% – A3. NU in pts with PU was significantly higher than in AU<30 mg/g. PDU in groups with different AU/PU was equally high and has no differ between DM types. Direct correlation was obtained between NU and AU (R=0,947 p<0,05). NU and PdU in T1DM correlated directly with serum creatinine (R=0,489 p<0,05 and R=0,468 p<0,05) and indirectly with GFR (R=-0,461 p<0,05 and R=-0,36 р<0,05). In DM duration less than 5 years NU directly correlated with НbА1с level, in T2DM – indirectly with systolic blood pressure.CONCLUSON. Nephrin and podocin levels can be useful for early diagnostics and monitoring of DN.

Sodium hydrogen sulfide (NaHS) ameliorates alterations caused by cisplatin in filtration slit diaphragm and podocyte cytoskeletal in rat kidney.

Background: Hydrogen sulfide (H2S) has been shown to have a protective role in various kidney disorders. Objectives: This study investigated the molecular mechanism of NaHS (a H2S donor) in treating on the renal damage induced by cisplatin (CP).Materials and Methods: Thirty-two male rats were randomly divided into 4 groups: Normal control group (group A)‚ NaHS group (group B) which received 200 µg/kg/d (intraperitoneal injection; i.p.) for 15 days‚ CP group (group C) which rats were injected with CP (5 mg/kg, single dose, i.p.), and CP + NaHS group (group D) (5 mg/kg and 200 µg/kg, respectively, i.p.). Samples of urine and serum, tissue of kidney were collected for analysis after treatments for 15 days. Morphological changes were elevated under light microscope‚ protein expression of desmin and nephrin were determined by immunohistochemistry and western blotting and also malondialdehyde (MDA) level was determined by spectrophotometer. Results: Compared to the CP group, NaHS treatment mitigated histological damages, decreased 24-hour urine protein excretion, serum urea and creatinine as well as MDA level. NaHS treatment increased protein levels of nephrin. Moreover, NaHS treatment decreased protein levels of desmin. Conclusions: NaHS can ameliorate CP -induced renal damage in rats which is associated with the increase in nephrin protein expression, and the decrease in MDA level and desmin protein expression.

Endoplasmic reticulum stress inhibition attenuates hypertensive chronic kidney disease through reduction in proteinuria

Endoplasmic reticulum (ER) stress is implicated in chronic kidney disease (CKD) development in patients and in animal models. Here we show that ER stress inhibition through 4-phenylbutyric acid (4-PBA) administration decreases blood pressure, albuminuria, and tubular casts in an angiotensin II/deoxycorticosterone acetate/salt murine model of CKD. Lower albuminuria in 4-PBA-treated mice was associated with higher levels of cubilin protein in renal tissue membrane fractions. 4-PBA decreased renal interstitial fibrosis, renal CD3+ T-cell and macrophage infiltration, mRNA expression of TGFβ1, Wnt signaling molecules, and ER stress-induced pro-inflammatory genes. CHOP deficient mice that underwent this model of CKD developed hypertension comparable to wild type mice, but had less albuminuria and tubular casts. CHOP deficiency resulted in higher nephrin levels and decreased glomerulosclerosis compared to wild type mice; this effect was accompanied by lower macrophage infiltration and fibrosis. Our findings portray ER stress inhibition as a means to alleviate hypertensive CKD by preserving glomerular barrier integrity and tubular function. These results demonstrate ER stress modulation as a novel target for preserving renal function in hypertensive CKD.

The Level of Serum and Urinary Nephrin in Normal Pregnancy and Pregnancy with Subsequent Preeclampsia

PurposeThe aim of this study was to evaluate serum and urinary nephrin levels of normal pregnancy to establish a standard reference value and to compare them with patients who subsequently developed preeclampsia (PE).Materials and MethodsIn this prospective study, 117 healthy singleton pregnancies were enrolled between 6 to 20 weeks of gestation at 2 participating medical centers during October 2010 to March 2012. Urine and serum samples were collected at the time of enrollment, each trimester, and at 4 to 6 weeks postpartum. Enzyme-linked immunosorbent assay for nephrin was performed and samples from patients who subsequently developed PE were compared to the normal patients.ResultsOf 117 patients initially enrolled, 99 patients delivered at the study centers and of those patients, 12 (12.1%) developed PE at a median gestational age of 34+4 weeks (range 29+5–36+6). In the normal patients (n=68), serum nephrin level decreased and urinary nephrin level increased during the latter of pregnancy. In 12 patients who subsequently developed PE, a significant rise in the 3rd trimester serum and urinary nephrin levels, compared to the controls, was observed (p<0.001), and this increase occurred 9 days prior to the onset of clinical disease.ConclusionAs the onset of PE was preceded by the rise in the serum and urinary nephrin in comparison to normal pregnancy, serum and urinary nephrin may be a useful predictive marker of PE.

Role of MiR-155 Signal Pathway in Regulating Podocyte Injury Induced by TGF-β1

Background/Aims: Transforming growth factor beta 1 (TGF-β1) plays a critical role in the pathogenesis of glomerulosclerosis. The purpose of this study was to examine the effects of inhibition of miR-155 on podocyte injury induced by TGF-β1 and to determine further molecular mediators involved in the effects of miR-155. Methods: Conditionally immortalized podocytes were cultured in vitro and they were divided into four groups: control; TGF-β1 treatment; TGF-β1 with miR-155 knockdown [using antisense oligonucleotides against miR-155 (ASO-miR-155)] and TGF-β1 with negative control antisense oligonucleotides (ASO-NC). Real time RT-PCR and Western blot analysis were employed to determine the mRNA and protein expression of nephrin, desmin and caspase-9, respectively. Flow cytometry was used to examine the apoptotic rate of podocytes and DAPI fluorescent staining was used to determine apoptotic morphology. In addition, we examined the levels of miR-155, TGF-β1, nephrin, desmin and caspase-9 in glomerular tissues of nephropathy induced by intravenous injections of adriamycin in rats. Results: mRNA and protein expression of desmin and caspase-9 was increased in cultured TGF-β1-treated podocytes, whereas nephrin was decreased as compared with the control group. Importantly, miR-155 knockdown significantly attenuated upregulation of desmin and caspase-9, and alleviated impairment of nephrin induced by TGF-β1. Moreover, the number of apoptotic podocytes was increased after exposure to TGF-β1 and this was alleviated after miR-155 knockdown. Knocking down miR-155 also decreased an apoptosis rate of TGF-β1-treated podocytes. Note that negative control antisense oligonucleotides failed to alter an increase of the apoptosis rate in TGF-β1-treated podocytes. Consistent with in vitro results, expression of miR-155, TGF-β1, desmin and caspase-9 was increased and nephrin was decreased in glomerular tissues with nephropathy in vivo experiments. Conclusions: TGF-β1 impairs the protein expression of nephrin and amplifies the protein expression of desmin and caspase -9 via miR-155 signal pathway. Inhibition of miR-155 alleviates these changes in podocytes-treated with TGF-β1 and attenuated apoptosis of podocytes. Our data suggest that miR-155 plays a role in mediating TGF-β1-induced podocyte injury via nephrin, desmin and caspase-9. Results of the current study also indicate that blocking miR-155 signal has a protective effect on podocyte injury. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of podocyte injury observed in glomerulosclerosis.

Early Renal Disease in Children with Sickle Cell Disease from Malawi

Sickle cell nephropathy (SCN) is a prevalent complication among adults with sickle cell disease (SCD) and has been observed in younger populations, suggesting potential early renal involvement in pediatric patients. Initial hyperfiltration and albuminuria followed by frank proteinuria, leading to declining GFR and eventual end stage renal disease is assumed to be the typical progression of SCN; however, few clinical biomarkers exist to identify early-stage renal disease. We describe the renal profile in 119 children with SCD at Kamuzu Central Hospital in Lilongwe, Malawi and propose a novel urinary biomarker for the identification of children with early renal disease. Among children with confirmed HbSS disease (females 47.9%; median age 9.0 years, IQR: 5, 11), 21.6% were found to have a urinary albumin to creatinine ratio (UACR) 30mg/g or above. Baseline laboratory and clinical parameters stratified by UACR are shown in Tables 1 and 2. Patients with increased levels of UACR were found to be significantly older, and have significantly elevated plasma levels of lactate dehydrogenase (LDH), total bilirubin, and indirect bilirubin when compared to those without albuminuria (p<0.05). No association was seen between albuminuria and either hemoglobin or plasma hemoglobin. Albuminuria was also significantly associated with elevated levels of nephrin, a urinary marker of glomerular injury (p<0.01). Multivariable logistic regression was used to investigate risk factors that are associated with albuminuria (UACR >= 30). Urine nephrin was significantly associated with albuminuria (regression coefficient estimate: 0.00188, SE: 0.000571, p = 0.0010). Additional analysis using a nephrin cut-point of 293 pg/mL, the median value in the cohort, revealed a 17.8 times greater odds of having albuminuria in children with nephrinuria above this value. These data taken together suggests that a significant proportion of children with SCD in Malawi exhibit renal involvement early in life and could be at risk for worsening nephropathy and end-stage renal disease as they grow older. Our data further indicates that urinary nephrin could be utilized as an early marker of glomerular disease in SCN and possibly prompt earlier intervention in these children. The discordant association of albuminuria with clinical markers of hemolysis suggests that hemolysis may not play a substantial role in the pathogenesis of albuminuria in this population. Increased surveillance of children with SCD for renal complications can ultimately inform management strategies to improve outcomes and increase life expectancy among children with SCD. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Silencing of Histone Deacetylase 9 Expression in Podocytes Attenuates Kidney Injury in Diabetic Nephropathy.

Podocyte dysfunction is important in the onset and development of diabetic nephropathy (DN). Histone deacetylases (HDACs) have been recently proved to play critical roles in the pathogenesis of DN. As one subtype of the class IIa HDACs, HDAC9 is capable to repress/de-repress their target genes in tumor, inflammation, atherosclerosis and metabolic diseases. In the present study, we investigate whether HDAC9 is involved in the pathophysiologic process of DN, especially the podocyte injury. Firstly, we explored the expression patterns and localization of HDAC9 and found that HDAC9 expression was significantly up-regulated in high glucose (HG)-treated mouse podocytes, as well as kidney tissues from diabetic db/db mice and patients with DN. Secondly, knockdown of HDAC9 in mouse podocytes significantly suppressed HG-induced reactive oxygen species (ROS) generation, cell apoptosis and inflammation through JAK2/STAT3 pathway and reduced the podocytes injury by decreasing the expression levels of Nephrin and Podocin. Moreover, in diabetic db/db mice, silencing of HDAC9 attenuated the glomerulosclerosis, inflammatory cytokine release, podocyte apoptosis and renal injury. Collectively, these data indicate that HDAC9 may be involved in the process of DN, especially podocyte injury. Our study suggest that inhibition of HDAC9 may have a therapeutic potential in DN treatment.

Intrarenal macrophage infiltration induced by T cells is associated with podocyte injury in lupus nephritis patients.

Proteinuria is the hallmark of clinical manifestation of disease activity in lupus nephritis (LN) patients, which arises from direct or indirect podocyte injury. This study is to explore the relationship between intrarenal T cell infiltration and podocyte injury in lupus nephritis (LN), and to understand the potential mechanisms of podocyte injury induced by intrarenal T cells. Sixty renal biopsies from patients diagnosed with LN were included in the present study. Histological changes in LN patients were detected by light and electron microscopy. Podocyte-specific nephrin expression in renal tissues was detected by immunofluorescence. Infiltration of T cells (CD3+ cells), infiltration of macrophages (CD68+ cells) and the expression of osteopontin (OPN) in renal tissues were examined by immunohistochemical staining. Pearson or Spearman's tests were used to perform correlation analysis. Morphologic lesions of podocytes were more severe in LN patients than in normal control subjects. Compared with normal control subjects, nephrin expression was significantly decreased in LN patients. The expression level of nephrin was significantly lower in active LN patients than in the inactive group of patients (P < 0.05). Compared with normal control subjects, the number of infiltrated intrarenal T cells and macrophages was significantly increased in LN patients. T cells were mainly distributed in renal interstitium, with very few being in glomeruli, while macrophages were mainly located in glomeruli. The number of intrarenal infiltrated T cells and macrophages in active LN patients was more than that in the inactive group (P < 0.05). Compared with normal control subjects, OPN expression in LN patients was increased significantly. The expression level of OPN in active LN patients was significantly higher than that in the inactive group (P < 0.05). Podocyte-specific nephrin was negatively correlated with 24-hour proteinuria, intrarenal T cells infiltration and intrarenal OPN expression in LN patients (P < 0.001). Intrarenal macrophages had significantly positive correlation with intrarenal OPN expression (P < 0.001). The present study provides possible links between intrarenal T cells, OPN, macrophages with reduced podocyte-nephrin and podocytopathy in systemic lupus erythematosus. In addition, infiltration of macrophages in glomeruli induced by OPN that is induced by T cells may be a crucial mechanism for podocyte injury.

Knockdown of ApoL1 in Zebrafish Larvae Affects the Glomerular Filtration Barrier and the Expression of Nephrin.

APOL1, a secreted high-density lipoprotein, is expressed in different human tissues. Genetic variants of APOL1 are described to be associated with the development of end stage renal diseases in African Americans. In human kidney, APOL1 is mainly expressed in podocytes that are responsible for proper blood filtration. Since mice do not express ApoL1, the zebrafish is an ideal model to study the role of ApoL1. Injection of morpholinos against zApoL1 into zebrafish eggs and larvae, respectively, induces severe edema indicating a leakage of the filtration barrier. This was demonstrated in zApoL1 knockdown larvae by intravascular injection of fluorescently-labeled 10- and 500-kDa dextrans and by clearance of the vitamin D-binding protein from the circulation. Immunohistochemistry and RT-PCR revealed the reduction of nephrin, a podocyte-specific protein essential for blood filtration. Coinjection of human nephrin mRNA rescued the zApoL1 knockdown induced phenotype. Reduced APOL1 and nephrin levels were also found in biopsies of patients suffering from end stage renal diseases. Our results demonstrate that zApoL1 is essential for proper blood filtration in the zebrafish glomerulus and that zApoL1 affects the expression of nephrin.

DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury

Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.

Protective effects of astragaloside in rats with adriamycin nephropathy and underlying mechanism

The present study was designed to determine the mechanism underlying the treatment of nephrotic syndrome using astragaloside by observing the effects of astragaloside on the expression of nephrin and podocin proteins and genes in kidneys of rats with adriamycin nephropathy. The rats were injected with adriamycin and, after successful model establishment, randomly divided into a model group, a Methylprednisolone (MP) group, and an astragaloside group. The 24-h complete urine samples were collected. Biochemical indicators were monitored, and kidney tissues were collected for pathological analysis using light microscopy and electron microscopy. The mRNA expression of nephrin and podocin was measured in the kidney tissues using the real-time qPCR, and the protein expression levels of nephrin and podocin were detected using Western blot analysis. At the end of 12 weeks of drug intervention, the urinary protein level was lower in the MP and astragaloside groups than that in the model group (P = 0.008 and P = 0.01, respectively). Serum albumin was higher in the MP and astragaloside groups than in the model group (P < 0.001 and P = 0.012, respectively). Podocytes in the MP group were nearly normal, and fusion of podocytes in the astragaloside group was significantly less than that in the control group. The nephrin and podocin mRNA and protein expression levels in the intervention groups were higher (P < 0.05) than that in the model group. Due to the increased expression of podocyte-related nephrin and podocin proteins, astragaloside maintained slit diaphragm integrity and decreased the level of proteinuria in rats with adriamycin nephropathy.

Treatment with irbesatan may improve slit diaphragm alterations in rats with adriamycin-induced nephropathy.

Objective:The study aimed to evaluate the effects of oral administration of irbesartan in adriamycin-induced nephropathy considering laboratory changes, kidney histology, and expression of proteins related to slit diaphragm and cytoskeleton of the podocyte.Methods:The animals were divided into control, model, methylprednisolone (MP), and irbesartan groups. The 24-hour urinary protein and biochemical indicators were determined, and renal pathological changes were observed. The mRNA and protein expression of nephrin, podocin, CD2-associated protein (CD2AP), and desmin in the kidney tissue were analyzed.Results:The urinary protein excretion levels in the MP and irbesartan groups were lower than those in the model group (p<0.01). Electron microscopy showed that fusion of the glomerular foot processes of the rats in the irbesartan group was significantly reduced. The mRNA and protein expression levels of nephrin and podocin in the renal tissue in the MP and irbesartan groups were up-regulated compared with the model group (p<0.05), whereas the mRNA and protein expression levels of CD2AP and desmin were significantly down-regulated (p<0.01).Conclusions:For rats with adriamycin-induced nephropathy, irbesartan could significantly reduce proteinuria. As a possible mechanism, irbesartan may improve the slit diaphragm protein of the glomerular podocyte and stabilize the cytoskeleton of the podocyte.

Urinary dedifferentiated podocytes as a non-invasive biomarker of lupus nephritis.

Currently, renal biopsy remains the gold standard for the diagnosis and prognosis of lupus nephritis (LN). However, it is an invasive method, and new non-invasive laboratory tests are needed to identify renal involvement without renal biopsy. Podocyte damage plays an important role in the pathogenesis and progression of systemic lupus erythematosus (SLE). We characterize whether the phenotype of urinary podocytes (viability, apoptosis, mRNA and protein levels of the podocyte-associated molecules) is a novel marker of clinical and histological features in SLE patients with or without LN. We quantified in urinary sediments of 32 SLE patients and 20 controls, mRNA and protein levels of podocalyxin, synapotopodin, podocin, nephrin and WT-1 by quantitative real-time polymerase chain reaction and western blot analysis and correlated these with clinical and histological parameters. The viability of detached urine podocytes was analysed by flow cytometry with podocalyxin and annexin V/7-AAD double staining and immunofluorescence of urine podocyte cultures. The degree of a poptotic podocytes from urine samples was significantly decreased in patients with LN, especially in the active state (33% compared with 75% in controls, P < 0.001), and the majority of the detached podocytes in the urine of patients with active LN were viable (70% grew in culture). Furthermore, urinary mRNA of podocyte-associated molecules was significantly lower in patients with active LN (P < 0.05) compared with healthy controls, and protein levels of podocyte markers were significantly increased in SLE patients, especially with LN compared with SLE without LN (P < 0.05) and the healthy control group (P < 0.01). Finally, urinary protein levels of podocyte-related markers were associated with proteinuria and histological features (P < 0.05 and P < 0.01), and receiver operating characteristics curves of protein levels discriminate between LN and healthy controls with an area under the curve (AUC) between 0.91 and 0.77 (P < 0.001). Urinary dedifferentiated podocytes were shown in active LN, and their protein levels correlated with proteinuria and histological features in LN. These preliminary results suggest that it could be a potentially useful non-invasive marker for evaluating the progression of glomerular disease in SLE.

MicroRNA-218 promotes high glucose-induced apoptosis in podocytes by targeting heme oxygenase-1

Emerging evidence has demonstrated that microRNAs (miRNAs) play a mediatory role in the pathogenesis of diabetic nephropathy. In this study, we found that miR-218 was upregulated in high glucose (HG) treated podocytes, which are essential components of the glomerular filtration barrier and a major prognostic determinant in diabetic nephropathy. Additionally, up-regulation of miR-218 was accompanied by an increased rate of podocyte death and down-regulation in the level of nephrin, a key marker of podocytes. However, inhibition of miR-218 exerted the opposite effect. In addition, the dual-luciferase reporter assay showed that miR-218 directly targeted the 3′-untranslated region of heme oxygenase-1 (HO-1), and further study confirmed an increase of HO-1 in HG-treated podocytes transfected with anti-miR-218. Knockdown of HO-1 blocked the anti-apoptotic effect of anti-miR-218. Furthermore, inhibition of miR-218 was associated with decreased expression of the known pro-apoptotic molecule p38-mitogen-activated protein kinase (p38-MAPK) activation. Following preconditioning with SB203580, an inhibitor of p38-MAPK, the stimulatory effect of HG on podocyte apoptosis was strikingly ameliorated. These findings suggested that miR-218 accelerated HG-induced podocyte apoptosis through directly down-regulating HO-1 and facilitating p38-MAPK activation.

Data supporting the regulation of FOXC2 in podocyte dysfunction.

This data article shows the expression levels of specific podocyte injury markers and podocyte slit diaphragm protein nephrin in obese and lean Zucker rat glomeruli. It also contains information on the effect of the overexpression of transcription factor FOXC2 on the ratio of F- and G-actin and the expression level of ZO-1 in differentiated human podocytes. The article also shows data on the effect of treatments of differentiated podocytes with various factors associated with obesity and diabetes on the expression level of FOXC2. The detailed interpretation of these data and other aspects of podocyte injury mediated by upregulation of FOXC2 can be found in “Overexpression of transcription factor FOXC2 in cultured human podocytes upregulates injury markers and increases motility [1].

The effect of pentoxifylline on the glomerular function in patients with severe pre-eclampsia

Introduction Pentoxifylline (PTX) is a phosphodiesterase inhibitor that directly upregulates the expression of vascular endothelial growth factor mRNA. Pre-eclampsia (PE) is a pregnancy-specific vascular endothelial disorder with a characteristic glomerular lesion, glomerular endotheliosis, that is due to vascular endothelial growth factor deprivation. This study aimed to investigate the effect of PTX on the functional manifestations of the glomerular endothelial injury in patients with severe PE. Patients and methods Forty patients with severe PE admitted to the Ain Shams Obstetric ICU were assigned randomly in the immediate postpartum period to one of two groups (20 in each group): the PTX group received a continuous intravenous infusion of PTX 400 mg every 8 h daily for 3 days; the control group received normal saline solution as placebo every 8 h daily for 3 days. The primary endpoint was the improvement of renal assessment data in the form of the serum creatinine level, the urine protein/creatinine (P/C) ratio, and urine nephrin levels. Results PTX administration in patients with severe PE was associated with significant reduction of urinary nephrin compared with baseline values (day 1) as well as with the values on day 3 in the control group ( P = 0.007 and P Conclusion The current study demonstrates that PTX administration to patients with severe PE, as an additional treatment to standard therapy on admission to the ICU, exhibits a renoprotective effect.

Urinary podocalyxin and nephrin levels as biomarkers in lupus nephritis patients: Relation to renal involvement and disease activity

Aim of the workTo evaluate the impact of systemic lupus erythematosus (SLE) on urinary levels of podocalyxin and nephrin and to determine their relationship to renal biopsy and disease activity in lupus nephritis (LN) patients. Patients and methodsThe study included 50 LN patients with their renal biopsy classified according to the international society of nephrology. Disease activity was determined using the British Isles Lupus Assessment Group (BILAG). All patients underwent clinical and laboratory evaluation. Urine samples were collected for the assessment of urinary podocalyxin (UPx) and nephrin (UN) by ELISA and for the estimation of protein (UP) and creatinine (Cr) concentrations. The UPx:Cr, UN:Cr and UP:Cr ratios were calculated. ResultsUrinary levels of podocalyxin (593.8±282.2ng/ml), nephrin (304.1±236.8ng/ml) and protein (2.36±0.56g/l) were significantly higher, while urinary creatinine levels (101.4±28.7mg/l) lower in LN patients compared to control (38.1±9ng/ml, 19.2±4.1ng/ml, 0.34±0.13g/l and 155.4±26.7mg/l; p=0.0008, p=0.0003, p=0.00002 and 0.0009, respectively). Consequently, UNCr, UPxCr and UPCr ratios were significantly higher in patients compared to control. There was a significant correlation of the estimated ratios with the LN class and with the BILAG scores being most significant with UPx:Cr ratio. ROC curve and regression analyses defined UPx:Cr ratio as the specific significant predictor of pathological LN grade. ConclusionSLE deleteriously affects fine glomerular structure as reflected by increased urinary levels of podocyte-related proteins; podocalyxin and nephrin. Urinary podocalyxin/creatinine ratio significantly predicts the pathological impact of SLE on the kidney and could be used as a non-invasive marker for such effect and its progression.

Increased urinary levels of podocyte glycoproteins, matrix metallopeptidases, inflammatory cytokines, and kidney injury biomarkers in women with preeclampsia.

To investigate kidney injury in preeclampsia, we analyzed 14 biomarkers in urine specimen from 4 groups of pregnant women (normotensive pregnant women and those with pregnancy complicated with chronic hypertension or mild or severe preeclampsia). These biomarkers included 1) podocyte glycoproteins nephrin and podocalyxin, 2) matrix metallopeptidase (MMP)-2 and MMP-9 and their inhibitor tissue inhibitor of metalloproteinase-2, 3) inflammatory molecules and cytokines soluble VCAM-1, TNF-α, soluble TNF receptor receptor-1, IL-6, IL-8, IL-10, and IL-18, and 4) kidney injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Postpartum urine specimens (6-8 wk) from normotensive women and those with severe preeclampsia were also evaluated. We found that, first, urine levels of nephrin, MMP-2, MMP-9, and kidney injury molecule-1 were significantly higher before delivery in severe preeclampsia than normotensive groups. The increased levels were all reduced to levels similar to those of the normotensive control group in postpartum specimens from the severe preeclampsia group. Second, soluble VCAM-1, soluble TNF receptor-1, and neutrophil gelatinase-associated lipocalin levels were significantly increased in the severe preeclampsia group compared with the normotensive control group before delivery, but levels of these molecules were significantly reduced in postpartum specimens in both groups. Third, IL-6 and IL-8 levels were not different between preeclampsia and normotensive groups but significantly increased in pregnancy complicated with chronic hypertension. Finally, tissue inhibitor of metalloproteinase-2 and IL-18 levels were not different among the study groups before delivery but were significantly reduced in postpartum specimens from normotensive controls. Our results indicate that the kidney experiences an increased inflammatory response during pregnancy. Most interestingly, tubular epithelial cell injury may also occur in severe preeclampsia. These biomarkers could be used to assess podocyte or tubular injury and kidney inflammatory responses during pregnancy and to evaluate postpartum kidney injury recovery in pregnancy-complicated disorders.

Protective Effects of Dimedone Pyrone on Podocytes in Rats with Diabetic Nephropathy

Purpose: To investigate the effect of dimedone pyrone (DP) on podocytes in rats with diabetic nephropathy (DN).Methods: The rats were randomly assigned into 5 experimental groups (n = 10), viz, non-diabetic control with no treatment (ND/NT), diabetic with no treatment (DG/NT), diabetic treated with 5 mg/kg dimedone pyrone (DG/DP 5), diabetic treated with 10 mg/kg dimedone pyrone (DG/DP 10) and diabetic treated with 20 mg/kk dimedone pyrone (DG/DP 20) group. Clinical parameters, including 24 h urinary protein, blood urea nitrogen (BUN), serum creatinine (SCR), blood glucose (GLU), and kidney weight (KW)/body weight (BW) were determined after 12 weeks of treatment. Hematoxylin and eosin staining was used to examine renal pathological changes while transmission electron microscopy (TEM) was employed for evaluation of structural changes in the podocytes. The expression levels of nephrin and podocin were evaluated using immunofluorescence staining.Results: Dimedone pyrone caused a significant decrease in SCR, BUN, GLU, KW/BW and 24 h urine protein in DG/DP 20 group compared to DG/NT group. Furthermore, incidences of glomerular disorders, chronic tubulo-interstitial damage and glomerular podocyte lesions decreased significantly following dimedone pyrone treatment. Glomeruli, tubules and podocytes exhibited pathomorphological improvements while nephrin and podocin protein expression levels were significantly higher in the nephridial tissue. Decrease in relative kidney weight (KW/BW) and 24 h urinary protein level were improved significantly on treatment with dimedone pyrone. Moreover, glomerular disorder, chronic tubulo-interstitial damage and glomerular podocyte lesions were also suppressed. The improvement was more significant in DG/DP 20 compared to DG/DP 5 and DG/DP 10 groups.Conclusion: Dimedone pyrone exhibits a protective effect on the podocytes of rats and may be of therapeutic importance in the treatment of diabetic nephropathy.Keywords: Dimedone pyrone, Podocin, Diabetic neuropathy, Nephrin, Glomerular disorders