nephrin and Acute-Kidney-Injury

Oxidative stress has been reported to play a critical role in the pathology of acute renal failure (ARF). An interaction between different reactive species and/or their sources have been the focus of extensive studies. The exact sources of reactive species generated in biological systems under different disease states are always elusive because they are also a part of physiological processes. Exaggerated involvement of different oxidation pathways including NAD(P)H oxidase has been proposed in different models of ARF. An interaction between oxygen species and nitrogen species has drawn extensive attention because of the deleterious effects of peroxynitrite and their possible effects on antioxidant systems. Recent advances in molecular biology have allowed us to understand glomerular function more precisely, especially the organization and importance of the slit diaphragm. Identification of slit diaphragm proteins came as a breakthrough and a possibility of therapeutic manipulation in ARF is encouraging. Transcriptional regulation of the expression of slit diaphragm protein is of particular importance because their presence is crucial in the maintenance of glomerular function. This review highlights the involvement of oxidative stress in ARF, sources of these reactive species, a possible interaction between different reactive species, and involvement of PPARgamma, a nuclear transcription factor in this process.

Topics: Acute Kidney Injury; Animals; Free Radicals; Gene Expression Regulation; Glomerular Basement Membrane; Humans; Membrane Proteins; Models, Biological; Nitric Oxide; Oxidative Stress; PPAR gamma; Reactive Nitrogen Species; Reactive Oxygen Species

The present study aimed to investigate the interaction between early diabetes and renal IR-induced AKI and to clarify the mechanisms involved. C57BL/6J mice were assigned to the following groups: (1) sham-operated; (2) renal IR; (3) streptozotocin (STZ-55 mg/kg/day) and sham operation; and (4) STZ and renal IR. On the 12th day after treatments, the animals were subjected to bilateral IR for 30 min followed by reperfusion for 48 h, at which time the animals were euthanized. Renal function was assessed by plasma creatinine and urea levels, as well urinary protein contents. Kidney morphology and gene and protein expression were also evaluated. Compared to the sham group, renal IR increased plasma creatinine, urea and albuminuria levels and decreased Nphs1 mRNA expression and nephrin and WT1 protein staining. Tubular injury was observed with increased Havcr1 and Mki67 mRNA expression accompanied by reduced megalin staining. Renal IR also resulted in increased SQSTM1 protein expression and increased proinflammatory and profibrotic factors mRNA expression. Although STZ treatment resulted in hyperglycemia, it did not induce significant changes in renal function. On the other hand, STZ treatment aggravated renal IR-induced AKI by exacerbating renal dysfunction, glomerular and tubular injury, inflammation, and profibrotic responses. Thus, early diabetes constitutes a relevant risk factor for renal IR-induced AKI.

Topics: Acute Kidney Injury; Albuminuria; Animals; Biomarkers; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Progression; Gene Expression; Ischemia; Kidney; Kidney Tubules; Membrane Proteins; Mice, Inbred C57BL; Reperfusion Injury; Risk Factors; Sequestosome-1 Protein

Arthrospira maxima (Spirulina) is a cyanobacterium which is considered a nutraceutical because it has antioxidant, anti-inflammatory, and cytoprotective properties in different renal disease models (Rodriguez-Sánchez et al., 2012; Aziz et al., 2018; Memije-Lazaro et al., 2018). The therapeutic effects are due to the presence of metabolites with biological effects similar to those of essential fatty acids ω-3 and ω-6, vitamins A, C and E, and accessory pigments such as phycobiliproteins. One of the most abundant phycobiliproteins in A. maxima is C-phycocyanin (Mysliwa-Kurdziel and Solymosi, 2017). This molecule is responsible for nephroprotective action in a model of acute kidney injury (AKI) because it reduces oxidative stress and caspase activation (Rodriguez-Sánchez et al., 2012; Rojas-Franco et al., 2018). However, both A. maxima and its C-phycocyanin are related to the reduction of the redox environment. Thus, they probably help to maintain the adequate function of the intracellular organelles like the endoplasmic reticulum. However, this therapeutic action has not been evaluated previously.

Topics: Acute Kidney Injury; Animals; Antioxidants; Endoplasmic Reticulum Stress; Gene Expression Profiling; Gene Expression Regulation; Intracellular Signaling Peptides and Proteins; Kidney; Male; Membrane Proteins; Mice; Oxidation-Reduction; Oxidative Stress; Phycocyanin; Spirulina

B-cell lymphoma/leukaemia 10 (Bcl10) is a member of the CARMA-Bcl10-MALT1 signalosome, linking angiotensin (Ang) II, and antigen-dependent immune-cell activation to nuclear factor kappa-B signalling. We showed earlier that Bcl10 plays a role in Ang II-induced cardiac fibrosis and remodelling, independent of blood pressure. We now investigated the role of Bcl10 in Ang II-induced renal damage.. Bcl10 knockout mice (Bcl10 KO) and wild-type (WT) controls were given 1% NaCl in the drinking water and Ang II (1.44 mg/kg/day) for 14 days. Additionally, Bcl10 KO or WT kidneys were transplanted onto WT mice that were challenged by the same protocol for 7 days. Kidneys of Ang II-treated Bcl10 KO mice developed less fibrosis and showed fewer infiltrating cells. Nevertheless, neutrophil gelatinase-associated lipocalin (Ngal) and kidney injury molecule (Kim)1 expression was higher in the kidneys of Ang II-treated Bcl10 KO mice, indicating exacerbated tubular damage. Furthermore, albuminuria was significantly higher in Ang II-treated Bcl10 KO mice accompanied by reduced glomerular nephrin expression and podocyte number. Ang II-treated WT mice transplanted with Bcl10 KO kidney showed more albuminuria and renal Ngal, compared to WT- > WT kidney-transplanted mice, as well as lower podocyte number but similar fibrosis and cell infiltration. Interestingly, mice lacking Bcl10 in the kidney exhibited less Ang II-induced cardiac hypertrophy than controls.. Bcl10 has multi-faceted actions in Ang II-induced renal damage. On the one hand, global Bcl10 deficiency ameliorates renal fibrosis and cell infiltration; on the other hand, lack of renal Bcl10 aggravates albuminuria and podocyte damage. These data suggest that Bcl10 maintains podocyte integrity and renal function.

Topics: Acute Kidney Injury; Albuminuria; Angiotensin II; Animals; B-Cell CLL-Lymphoma 10 Protein; Cell Movement; Disease Models, Animal; Fibrosis; Hepatitis A Virus Cellular Receptor 1; Kidney; Kidney Transplantation; Lipocalin-2; Macrophages; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; Podocytes; T-Lymphocyte Subsets; Time Factors

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal

Topics: Acute Kidney Injury; Adult; Child; Child, Preschool; Collagen Type IV; Female; Genetic Predisposition to Disease; Glomerulosclerosis, Focal Segmental; Hemizygote; Heterozygote; Humans; Infant; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mutation; Nephritis, Hereditary; Pedigree; Polymorphism, Single Nucleotide

Nephrin is a key component of the slit diaphragm of the glomerular podocyte, and increased urinary nephrin level may reflect glomerular injury.. To determine whether urinary nephrin is a useful biomarker of glomerular maturation and injury and whether it is associated with acute kidney injury (AKI) and neonatal intensive care unit (NICU) mortality in critically ill neonates.. Urinary samples were serially collected in 234 neonates during NICU stay for measurements of nephrin, cystatin C (CysC), and albumin. AKI diagnosis was based on neonatal Kidney Disease: Improving Global Outcome (KDIGO) criteria.. Of the neonates, 26 developed AKI and 24 died during NICU stay. The independent contributors to the initial urinary nephrin level obtained on the first 24 h admitted to NICU were gestational age (p = 0.004) and initial urinary CysC level (p < 0.001). Both initial (p = 0.037) and peak (p = 0.039) urinary nephrin were significantly associated with AKI, even after controlling for significant covariates, and had an area under the receiver-operating characteristic curve (AUC) of 0.71 and 0.70, respectively, for predicting AKI. At the optimal cutoff value of 0.375 μg/mg urinary creatinine, the initial urinary nephrin displayed sensitivity of 61.5% and specificity of 76.9% for predicting AKI. The AUCs for initial and peak urinary nephrin to predict NICU mortality were 0.81 and 0.83, respectively.. Urinary nephrin, which may decrease with increasing glomerular maturity, is significantly associated with increased risk for AKI and NICU mortality even after adjustment for potential confounders. A higher level of urinary nephrin may be independently predictive of AKI and NICU mortality in critically ill neonates.

Topics: Acute Kidney Injury; Area Under Curve; Biomarkers; Critical Illness; Cystatin C; Female; Gestational Age; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Length of Stay; Logistic Models; Male; Membrane Proteins; Multivariate Analysis; Predictive Value of Tests; Prospective Studies; ROC Curve

In this study, we developed a multilayer microfluidic device to simulate nephron, which was formed by "glomerulus", "Bowman's capsule", "proximal tubular lumen" and "peritubular capillary". In this microdevice, artificial renal blood flow was circulating and glomerular filtrate flow was single passing through, mimicking the behavior of a nephron. In this dynamic artificial nephron, we observed typical renal physiology, including the glomerular size-selective barrier, glomerular basement membrane charge-selective barrier, glucose reabsorption and para-aminohippuric acid secretion. To demonstrate the capability of our microdevice, we used it to investigate the pathophysiology of drug-induced acute kidney injury (AKI) and give assessment of drug-induced nephrotoxicity, with cisplatin and doxorubicin as model drugs. In the experiment, we loaded the doxorubicin or cisplatin in the "renal blood flow", recorded the injury of primary glomerular endothelial cells, podocytes, tubular epithelial cells and peritubular endothelial cells by fluorescence imaging, and identified the time-dependence, dose-dependence and the death order of four types of renal cells. Then by measuring multiple biomarkers, including E-cadherin, VEGF, VCAM-1, Nephrin, and ZO-1, we studied the mechanism of cell injuries caused by doxorubicin or cisplatin. Also, we investigated the effect of BSA in the "renal blood flow" on doxorubicin-or-cisplatin-induced nephrotoxicity, and found that BSA enhanced the tight junctions between cells and eased cisplatin-induced nephrotoxicity. In addition, we compared the nephron model and traditional tubule models for assessment of drug-induced nephrotoxicity. And it can be inferred that our biomimetic microdevice simulated the complex, dynamic microenvironment of nephron, yielded abundant information about drug-induced-AKI at the preclinical stage, boosted the drug safety evaluation, and provided a reliable reference for clinical therapy.

Topics: Acute Kidney Injury; Animals; Biological Transport; Cadherins; Cattle; Cisplatin; Doxorubicin; Kidney; Kidney Glomerulus; Kidney Tubules, Proximal; Membrane Proteins; Microfluidics; Nephrons; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Topics: Acute Kidney Injury; Animals; Apoptosis; Disease Models, Animal; Doxorubicin; Humans; Inflammation; Kidney Diseases; Male; Membrane Proteins; Mice; Oxidative Stress; Piperidones; Pyrimidines; Repressor Proteins; WT1 Proteins

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.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Blood Pressure; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Down-Regulation; Female; Flavonoids; Gestational Age; Hypertension, Pregnancy-Induced; Kidney; Membrane Proteins; NG-Nitroarginine Methyl Ester; Pregnancy; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Reproduction; Up-Regulation

Topics: Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Animals; Membrane Proteins; Mice; Oncogene Proteins; Phosphorylation; Podocytes; Tyrosine

Mutations in the INF2 (inverted formin 2) gene, encoding a diaphanous formin family protein that regulates actin cytoskeleton dynamics, cause human focal segmental glomerulosclerosis (FSGS). INF2 interacts directly with certain other mammalian diaphanous formin proteins (mDia) that function as RhoA effector molecules. FSGS-causing INF2 mutations impair these interactions and disrupt the ability of INF2 to regulate Rho/Dia-mediated actin dynamics in vitro. However, the precise mechanisms by which INF2 regulates and INF2 mutations impair glomerular structure and function remain unknown. Here, we characterize an Inf2 R218Q point-mutant (knockin) mouse to help answer these questions. Knockin mice have no significant renal pathology or proteinuria at baseline despite diminished INF2 protein levels. INF2 mutant podocytes do show impaired reversal of protamine sulfate-induced foot process effacement by heparin sulfate perfusion. This is associated with persistent podocyte cytoplasmic aggregation, nephrin phosphorylation, and nephrin and podocin mislocalization, as well as impaired recovery of mDia membrane localization. These changes were partially mimicked in podocyte outgrowth cultures, in which podocytes from knockin mice show altered cellular protrusions compared to those from wild-type mice. Thus, in mice, normal INF2 function is not required for glomerular development but normal INF2 is required for regulation of the actin-based behaviors necessary for response to and/or recovery from injury.

Topics: Actins; Acute Kidney Injury; Animals; Cells, Cultured; Disease Models, Animal; Formins; Glomerulosclerosis, Focal Segmental; Heparin; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Microfilament Proteins; Microscopy, Electron, Transmission; Phenotype; Phosphorylation; Podocytes; Point Mutation; Protamines; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; Signal Transduction

MiR-155 has been reported to be involved in both innate and adaptive immune responses. But the role of miR-155 in hyperglycemia-induced nephropathy is still unknown. In our current study, 3-month-old male wild-type C57 mice and Mir-155(-/-) mice were used to establish hyperglycemia-induced nephropathy. In our hyperglycemia-induced nephropathy model, the expression of podocyte injury marker desmin was markedly increased in the diabetes group when compared with control. Diabetes also significantly decreased the levels of nephrin and acetylated nephrin, whereas the expression of miR-155 was markedly increased in diabetes group when compared with control. MiR-155(-/-) mice showed significantly increased expression of nephrin, acetylated nephrin, and Wilm's tumor-1 protein (WT-1) when compared with wild-type control. MiR-155 deficiency results in significantly decrease in IL-17A expression both in vivo and in vitro. And the increased expression of WT-1, nephrin, and ac-nephrin was reversed with additional treatment of rmIL-17. Furthermore, we found that the inhibited Th17 differentiation induced by miR-155 deficiency was dependent on increased expression of SOCS1. In conclusion, miR-155 deficiency promotes nephrin acetylation and attenuates renal damage in hyperglycemia-induced nephropathy. This was associated with inhibited IL-17 production through enhancement of SOCS1 expression.

Topics: Acetylation; Acute Kidney Injury; Animals; Cell Differentiation; Desmin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Hyperglycemia; Interleukin-17; Kidney; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Podocytes; Repressor Proteins; Streptozocin; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins; Th17 Cells; WT1 Proteins

Hyperphosphatemia accelerates the progression of chronic kidney diseases. In the present study, the effects of ronacaleret, a calcilytic agent, on renal injury were assessed in the following four groups of rats: 5/6-nephrectomized Wistar rats as a control (C group), rats treated with ronacaleret (3 mg·kg(-1)·day(-1); R group), rats treated with calcitriol (30 ng·kg(-1)·day(-1); V group), and rats treated with both ronacaleret and calcitriol (R + V group). Three months later, rats were euthanized under anesthesia, and the remnant kidneys were harvested for analysis. Albuminuria was lower in the R and V groups than in the C group (P < 0.05). Creatinine clearance was elevated in the R and V groups compared with the C group (P < 0.05). Serum Ca(2+) and renal ANG II were higher in the R + V group than in the C group (P < 0.05 for each), and serum phosphate was reduced in the R group compared with the C group (P < 0.05). Fibroblast growth factor-23 was lower in the R group and higher in the V and R + V groups than in the C group. However, parathyroid hormone did not differ significantly among the four groups. Renal klotho expression was elevated in the R and V groups compared with the C group (P < 0.05). The present data indicate that ronacaleret preserves klotho expression and renal function with reductions in serum phosphate and albuminuria in 5/6-nephrectomized rats. Our findings demonstrate that vitamin D prevents declines in klotho expression and renal function, suppressing albuminuria.

Topics: Acute Kidney Injury; Albuminuria; Animals; Calcium Phosphates; Indans; Kidney; Male; Membrane Proteins; Nephrectomy; Phenylpropionates; Rats; Rats, Wistar; Receptors, Calcium-Sensing; Renal Artery; TRPC Cation Channels; Vitamin D

The study was aimed to estimate whether pre-treatment with sodium selenite or taurine would reverse kidney damage induced by intraperitoneal injection of mercuric chloride in rats. Animals were divided into six groups: (1) control group; (2) sodium selenite group; (3) taurine group; (4) HgCl2 group; (5) sodium selenite pretreated group; (6) taurine pretreated group. The results demonstrated that HgCl2 causes significant enhancement in serum malondialdehyde (MDA), creatinine, N-acetyl-beta-d-glucosaminidase (NAG), cystatin C, nephrin and interleukin 6 (IL-6) levels accompanied with significant reduction in serum nitric oxide (NO) level. Pretreatment with sodium selenite or taurine produces significant depletion in MDA, NAG, cystatin C, nephrin and IL-6 levels in concomitant with significant elevation in serum NO level as compared to HgCl2 group. HgCl2 induced pathological alterations in the kidney. The ultrastructural investigation of renal cortex of HgCl2-administered group revealed that the glomerular basement membrane is uniform, the fenestrations of endothelial cells are swollen, and the secondary foot processes appear also swollen even fused at some points. The proximal convoluted tubules showed apical short and few microvilli, while, some tubular cells showed relatively normal microvilli. In contrast, sodium selenite or taurine pretreatment could significantly reduce the pathological alterations in the kidney caused by HgCl2 intoxication. The current results suggested that selenium and taurine possess nephroprotective efficacy due to their antioxidative capacity and anti-inflammatory activity.

Topics: Acetylglucosaminidase; Acute Kidney Injury; Animals; Antioxidants; Creatinine; Cystatin C; Drug Evaluation, Preclinical; Interleukin-6; Kidney; Male; Malondialdehyde; Membrane Proteins; Mercuric Chloride; Nitric Oxide; Rats, Wistar; Sodium Selenite; Taurine

In view of increased vascular endothelial growth factor-A (VEGF-A) expression and renal dysfunction in early diabetes, we designed a study to test whether VEGF-A inhibition can prevent early renal injury and dysfunction. We investigated the relationship and mechanism between VEGF-A and AKT regulation. In vitro, VEGF-A small interfering RNA (siRNA) and AKT inhibitor MK-2206 were employed to podocytes and NRK-52 cells cultured in high glucose (30 mM). In vivo, the antiangiogenic drug endostatin was administered in 12 week-old streptozotocin-induced male Sprague Dawley rats. The levels of VEGF-A, AKT, phosphorylated Ser⁴⁷³-AKT, phosphorylated Thr³⁰⁸-AKT, nephrin, angiotensin II (Ang II), angiotensin type II receptor 1 (ATR1) were examined using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot analysis and immunohistochemistry. Interactions between phosphorylated Thr³⁰⁸-AKT and either nephrin in podocytes or Ang II in renal tubules were studied, respectively, using confocal immunofluorescence microscopy and immunoprecipitation. Silencing VEGF-A in podocytes upregulated phosphorylated Thr³⁰⁸-AKT and nephrin. Silencing VEGF-A in NRK-52E cells upregulated phosphorylated Thr³⁰⁸-AKT while downregulated Ang II and ATR1. MK-2206 enhanced VEGF-A expression in both podocytes and NRK-52E cells by inhibiting AKT activities. In diabetic rat kidneys, VEGF-A was upregulated and phosphorylated Thr³⁰⁸-AKT colocalized with either nephrin in podocytes or Ang II in renal tubules. With the endostatin treatment, the level of VEGF-A decreased while phosphorylated Thr³⁰⁸-AKT increased in both glomeruli and renal tubules. Treatment with endostatin upregulated nephrin in podocytes while downregulated Ang II and AT1R in renal tubules. Glomerular mesangial expansion was attenuated by the endostatin treatment, however, differences did not reach statistical significance. Endostatin ameliorated the interstitial fibrosis, urine albumin excretion rate (UAER) and albumin to creatinine ratio. We conclude that phosphorylated Thr³⁰⁸-AKT regulates VEGF-A expression by interacting with either nephrin in glomeruli or Ang II in renal tubules. Antiangiogenic treatment improves renal injury and function in early experimental diabetes.

Topics: Acute Kidney Injury; Angiogenesis Inhibitors; Angiotensin II; Animals; Cell Line; Diabetes Mellitus, Experimental; Endostatins; Heterocyclic Compounds, 3-Ring; Male; Membrane Proteins; Mice; Phosphorylation; Podocytes; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Small Interfering; Streptozocin; Vascular Endothelial Growth Factor A

Podocytes are highly specialized epithelial cells with complex actin cytoskeletal architecture crucial for maintenance of the glomerular filtration barrier. The mammalian Rho GTPases Rac1 and Cdc42 are molecular switches that control many cellular processes, but are best known for their roles in the regulation of actin cytoskeleton dynamics. Here, we employed podocyte-specific Cre-lox technology and found that mice with deletion of Rac1 display normal podocyte morphology without glomerular dysfunction well into adulthood. Using the protamine sulfate model of acute podocyte injury, podocyte-specific deletion of Rac1 prevented foot process effacement. In a long-term model of chronic hypertensive glomerular damage, however, loss of Rac1 led to an exacerbation of albuminuria and glomerulosclerosis. In contrast, mice with podocyte-specific deletion of Cdc42 had severe proteinuria, podocyte foot process effacement, and glomerulosclerosis beginning as early as 10 days of age. In addition, slit diaphragm proteins nephrin and podocin were redistributed, and cofilin was dephosphorylated. Cdc42 is necessary for the maintenance of podocyte structure and function, but Rac1 is entirely dispensable in physiological steady state. However, Rac1 has either beneficial or deleterious effects depending on the context of podocyte impairment. Thus, our study highlights the divergent roles of Rac1 and Cdc42 function in podocyte maintenance and injury.

Topics: Actin Depolymerizing Factors; Acute Kidney Injury; Albuminuria; Animals; cdc42 GTP-Binding Protein; Cell Shape; Desoxycorticosterone Acetate; Disease Models, Animal; Genotype; Hypertension; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Nephrectomy; Neuropeptides; Phenotype; Phosphorylation; Podocytes; Protamines; rac1 GTP-Binding Protein; Renal Insufficiency; Signal Transduction; Time Factors

Acute kidney injury (AKI) is a major complication for infants following an asphyxic insult at birth. We aimed to determine if kidney structure and function were affected in an animal model of birth asphyxia and if maternal dietary creatine supplementation could provide an energy reserve to the fetal kidney, maintaining cellular respiration during asphyxia and preventing AKI.. Pregnant spiny mice were maintained on normal chow or chow supplemented with creatine from day 20 gestation. On day 38 (term ~39 d), pups were delivered by cesarean section (c-section) or subjected to intrauterine asphyxia. Twenty-four hours after insult, kidneys were collected for histological or molecular analysis. Urine and plasma were also collected for biochemical analysis.. AKI was evident at 24 h after birth asphyxia, with a higher incidence of shrunken glomeruli (P < 0.02), disturbance to tubular arrangement, tubular dilatation, a twofold increase (P < 0.02) in expression of Ngal (early marker of kidney injury), and decreased expression of the podocyte differentiation marker nephrin. Maternal creatine supplementation prevented the glomerular and tubular abnormalities observed in the kidney at 24 h and the increased expression of Ngal.. Maternal creatine supplementation may prove useful in ameliorating kidney injury associated with birth asphyxia.

Topics: Acute Kidney Injury; Animals; Asphyxia Neonatorum; Biomarkers; Creatine; Cytoprotection; Dietary Supplements; Disease Models, Animal; Female; Gene Expression Regulation, Developmental; Gestational Age; Humans; Infant, Newborn; Kidney; Lipocalins; Membrane Proteins; Murinae; Pregnancy; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Time Factors

To investigate the injury effects of organic solvents on kidney, an animal model of Sprague-Dawley (SD) rats treated with mixed organic solvents via inhalation was generated and characterized. The mixed organic solvents consisted of gasoline, dimethylbenzene and formaldehyde (GDF) in the ratio of 2:2:1, and were used at 12,000 PPM to treat the rats twice a day, each for 3 hours. Proteinuria appeared in the rats after exposure for 5-6 weeks. The incidences of proteinuria in male and female rats after exposure for 12 weeks were 43.8% (7/16) and 25% (4/16), respectively. Urinary N-Acetyl-β-(D)-Glucosaminidase (NAG) activity was increased significantly after exposure for 4 weeks. Histological examination revealed remarkable injuries in the proximal renal tubules, including tubular epithelial cell detachment, cloud swelling and vacuole formation in the proximal tubular cells, as well as proliferation of parietal epithelium and tubular reflux in glomeruli. Ultrastructural examination found that brush border and cytoplasm of tubular epithelial cell were dropped, that tubular epithelial cells were partially disintegrated, and that the mitochondria of tubular epithelial cells were degenerated and lost. In addition to tubular lesions, glomerular damages were also observed, including segmental foot process fusion and loss of foot process covering on glomerular basement membrane (GBM). Immunofluorescence staining indicated that the expression of nephrin and podocin were both decreased after exposure of GDF. In contrast, increased expression of desmin, a marker of podocyte injury, was found in some areas of a glomerulus. TUNEL staining showed that GDF induced apoptosis in tubular cells and glomerular cells. These studies demonstrate that GDF can induce both severe proximal tubular damage and podocyte injury in rats, and the tubular lesions appear earlier than that of glomeruli.

Topics: Acetylglucosaminidase; Acute Kidney Injury; Animals; Apoptosis; Cytoskeleton; Female; Formaldehyde; Gasoline; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Kidney Tubules; Male; Membrane Proteins; Organ Specificity; Proteinuria; Rats; Rats, Sprague-Dawley; Solvents; Xylenes