The older plant gets the sun: Age‐related changes in Miscanthus × giganteus phenology

Age‐related changes are usually overlooked in perennial grass research; when they are considered it is usually as a change in plant size (e.g., biomass). Whether other physiological or developmental aspects change as stands age, and how those aspects may impact long‐term stand dynamics, remains unclear. Conventional experimental designs study a single stand over multiple growing seasons and thereby confound age‐related changes with growing season conditions. Here we used a staggered‐start experimental design with three repeated planting years over two growing seasons to isolate growing season effects. We studied changes in Miscanthus × giganteus phenology during its yield‐building stage (first 3 years) and estimated age, growing season and nitrogen (N) effects on development using nonlinear regression parameters. Stand age clearly changed plant growth; faster developmental rates were usually seen in 1‐year‐old stands (young), but because 2‐ and 3‐year‐old stands (mature) emerged 3 months earlier than newly planted stands they produced 30% more stems with 30%–60% more leaves. Nitrogen fertilization modulated some age‐related phenological changes. Fertilized 2‐year‐old stands reached similar stem densities as unfertilized 3‐year‐old stands and had fewer number of senesced leaves like 1‐year‐old stands. In addition, N fertilization had no effect on young M. × giganteus, but extended mature stands’ growing season more than 2 weeks by hastening emergence and delaying senescence. It also delayed flowering regardless of stand age. Our results suggest that, along with changes in size, M. × giganteus stands showed shifts in developmental strategies: young stands emerged later and developed faster, while mature stands grew for longer but more slowly. In temperate regions, where hard frost events are likely to interrupt development in late autumn, rapid early development is critical to plant survival. Nonlinear regression parameter differences proved effective in identifying phenological shifts.     

Curcumin alleviates acute kidney injury in a dry‐heat environment by reducing oxidative stress and inflammation in a rat model

Curcumin exhibits anti‐inflammatory and antioxidant activities. We investigated the protective effects of curcumin in a renal injury rat model under dry‐heat conditions. We divided Sprague‐Dawley rats into four groups: dry‐heat 0‐ (normal temperature control group), 50‐, 100‐, and 150‐minute groups. Each group was divided into five subgroups (n = 10): normal saline (NS), sodium carboxymethylcellulose (CMCNa), and curcumin pretreated low, medium, and high‐dose (50, 100, and 200 mg/kg, respectively) groups. Compared to the normal temperature group, serum creatinine, blood urea nitrogen, urinary kidney injury molecule‐1, and neutrophil gelatinase‐associated load changes in lipoprotein (NGAL) levels were significantly increased in the dry‐heat environment group (P < .05); inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2) expression and malondialdehyde (MDA) and related inflammatory factor levels were increased in the kidney tissue. Superoxide dismutase (SOD) and catalase (CAT) levels were decreased. However, following all curcumin pretreatment, the serum levels of kidney injury indicators and NGAL were decreased in the urine compared to those in the NS and CMCNa groups (P < .05), whereas renal SOD and CAT activities were increased and MDA was decreased (P < .05). Renal tissues of the 150‐minute group showed obvious pathological changes. Compared to the NS group, pathological changes in the renal tissues of the 100‐ and 200‐mg/kg curcumin groups were significantly reduced. Furthermore, iNOS and COX‐2 expression and inflammatory factor levels were decreased after curcumin treatment. Curcumin exerted renoprotective effects that were likely mediated by its antioxidant and anti‐inflammatory effects in a dry‐heat environment rat model.     

Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction

Renal fibrosis is the common pathological feature in a variety of chronic kidney diseases. Aging is highly associated with the progression of renal fibrosis. Among several determinants, mitochondrial dysfunction plays an important role in aging. However, the underlying mechanisms of mitochondrial dysfunction in age‐related renal fibrosis are not elucidated. Herein, we found that Wnt/β‐catenin signaling and renin–angiotensin system (RAS) activity were upregulated in aging kidneys. Concomitantly, mitochondrial mass and functions were impaired with aging. Ectopic expression of Klotho, an antagonist of endogenous Wnt/β‐catenin activity, abolished renal fibrosis in d ‐galactose (d ‐gal)‐induced accelerated aging mouse model and significantly protected renal mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species. In an established aging mouse model, dickkopf 1, a more specific Wnt inhibitor, and the mitochondria‐targeted antioxidant mitoquinone restored mitochondrial mass and attenuated tubular senescence and renal fibrosis. In a human proximal tubular cell line (HKC‐8), ectopic expression of Wnt1 decreased biogenesis and induced dysfunction of mitochondria, and triggered cellular senescence. Moreover, d ‐gal triggered the transduction of Wnt/β‐catenin signaling, which further activated angiotensin type 1 receptor (AT1), and then decreased the mitochondrial mass and increased cellular senescence in HKC‐8 cells and primary cultured renal tubular cells. These effects were inhibited by AT1 blocker of losartan. These results suggest inhibition of Wnt/β‐catenin signaling and the RAS could slow the onset of age‐related mitochondrial dysfunction and renal fibrosis. Taken together, our results indicate that Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction.     

Inhibiting the urokinase‐type plasminogen activator receptor system recovers STZ‐induced diabetic nephropathy

The urokinase‐type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR ‐(s)uPAR‐ from circulation) is to regulate podocyte function through αvβ3 integrin/Rac‐1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors (FPRs) can improve kidney lesions in a rat model of streptozotocin (STZ)‐induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, αvβ3 integrin/Rac‐1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ‐induced up‐regulation of uPA levels and activity, while uPAR on podocytes and (s)uPAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the αvβ3 integrin/Rac‐1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen‐plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/uPAR system as a promising target for the development of novel uPAR‐targeting approaches.     

The human urinary proteome reveals high similarity between kidney aging and chronic kidney disease

Aging induces morphological changes of the kidney and reduces renal function. We analyzed the low molecular weight urinary proteome of 324 healthy individuals from 2–73 years of age to gain insight on human renal aging. We observed age‐related modification of secretion of 325 out of over 5000 urinary peptides. The majority of these changes were associated with renal development before and during puberty, while 49 peptides were related to aging in adults. We therefore focussed the remainder of the study on these 49 peptides. The majority of these 49 peptides were also markers of chronic kidney disease, suggesting high similarity between aging and chronic kidney disease. Blinded evaluation of samples from healthy volunteers and diabetic nephropathy patients confirmed both the correlation of biomarkers with aging and with renal disease. Identification of a number of these aging‐related peptides led us to hypothesize that reduced proteolytic activity is involved in human renal aging. Finally, among the 324 supposedly healthy individuals, some had urinary aging‐related peptide excretion patterns typical of an individual significantly older than their actual age. In conclusion, these aging‐related biomarkers may allow noninvasive detection of renal lesions in healthy persons and show high resemblance between human aging and chronic kidney disease. This similarity has to be taken into account when searching for biomarkers of renal disease.     

Downregulation of ACE2 expression by SARS-CoV-2 worsens the prognosis of KIRC and KIRP patients via metabolism and immunoregulation

Background: Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) allow entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells and play essential roles in cancer therapy. However, the functions of ACE2 and TMPRSS2 in kidney cancer remain unclear, especially as kidneys are targets for SARS-CoV-2 infection.Methods: UCSC Xena project, the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases ({"type":"entrez-geo","attrs":{"text":"GSE30589","term_id":"30589"}}GSE30589 and {"type":"entrez-geo","attrs":{"text":"GSE59185","term_id":"59185"}}GSE59185) were searched for gene expression in human tissues, gene expression data, and clinical information. Several bioinformatics methods were utilized to analyze the correlation between ACE2 and TMPRSS2 with respect to the prognosis of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP).Results: ACE2 expression was significantly upregulated in tumor tissue, while its downregulation was associated with low survival in KIRC and KIRP patients. TMPRSS2 was downregulated in KIRC and KIRP, and its expression was not correlated with patient survival. According to clinical risk factor-based prediction models, ACE2 exhibits predictive accuracy for kidney cancer prognosis and is correlated with metabolism and immune infiltration. In an animal model, ACE2 expression was remarkably downregulated in SARS-CoV-2-infected cells compared to in the control.Conclusion: ACE2 expression is highly correlated with various metabolic pathways and is involved in immune infiltration.it plays a crucial role than TMPRSS2 in diagnosing and prognosis of kidney cancer patients. The overlap in ACE2 expression between kidney cancer and SARS-CoV-2 infection suggests that patients with KIRC or KIRP are at high risk of developing serious symptoms.     

Generation of easily accessible human kidney tubules on two‐dimensional surfaces in vitro

The generation of tissue‐like structures in vitro is of major interest for various fields of research including in vitro toxicology, regenerative therapies and tissue engineering. Usually 3D matrices are used to engineer tissue‐like structures in vitro, and for the generation of kidney tubules, 3D gels are employed. Kidney tubules embedded within 3D gels are difficult to access for manipulations and imaging. Here we show how large and functional human kidney tubules can be generated in vitro on 2D surfaces, without the use of 3D matrices. The mechanism used by human primary renal proximal tubule cells for tubulogenesis on 2D surfaces appears to be distinct from the mechanism employed in 3D gels, and tubulogenesis on 2D surfaces involves interactions between epithelial and mesenchymal cells. The process is induced by transforming growth factor‐β₁, and enhanced by a 3D substrate architecture. However, after triggering the process, the formation of renal tubules occurs with remarkable independence from the substrate architecture. Human proximal tubules generated on 2D surfaces typically have a length of several millimetres, and are easily accessible for manipulations and imaging, which makes them attractive for basic research and in vitro nephrotoxicology. The experimental system described also allows for in vitro studies on how primary human kidney cells regenerate renal structures after organ disruption. The finding that human kidney cells organize tissue‐like structures independently from the substrate architecture has important consequences for kidney tissue engineering, and it will be important, for instance, to inhibit the process of tubulogenesis on 2D surfaces in bioartificial kidneys.     

Reduced urinary excretion of sulfated polysaccharides in diabetic rats

The aim of the present study was to further understand the changes in renal filtration that occur in the early stages of diabetes mellitus. Diabetes was induced in male Wistar rats by a single injection of streptozotocin. Glycemia, body weight, 24-h urine volume and urinary excretion of creatinine, protein and glycosaminoglycans were measured 10 and 30 days after diabetes induction. All the diabetic animals used in the present study were hyperglycemic, did not gain weight, and presented proteinuria and creatinine hyperfiltration. In contrast, the glycosaminoglycan excretion decreased. Dextran sulfates of different molecular weights (6.0 to 11.5 kDa) were administered to the diabetic rats, and to age-matched, sham-treated controls. Most of the dextran sulfate was excreted during the first 24 h, and the amounts excreted in the urine were inversely proportional to the dextran sulfate molecular weight for all groups. Nevertheless, diabetic rats excreted less and accumulated more dextran sulfate in kidney and liver, as compared to controls. These differences, which were observed only for the dextran sulfates of higher molecular weights (>7 kDa), increased with the duration of diabetes. Our findings suggest differential renal processing mechanisms for proteins and sulfated polysaccharides, with the possible involvement of kidney cells.     

Kruppel‐like factor 4 improves obesity‐related nephropathy through increasing mitochondrial biogenesis and activities

Obesity is positively linked to multiple metabolic complications including renal diseases. Several studies have demonstrated Kruppel‐like factor 4 (KLF4) participated in renal dysfunction and structural disorders in acute kidney injuries, but whether it affected the process of chronic kidney diseases was unknown. Therefore, present study was to disclose the role of renal KLF4 in dietary‐induced renal injuries and underlying mechanisms in obesity. Through utilizing high‐fat diet‐fed mice and human renal biopsies, we provided the physiological roles of KLF4 in protecting against obesity‐related nephropathy. Decreased levels of renal KLF4 were positively correlated with dietary‐induced renal dysfunction, including increased levels of creatinine and blood urea nitrogen. Overexpression of renal KLF4 suppressed inflammatory response in palmitic acid‐treated mouse endothelial cells. Furthermore, overexpressed KLF4 also attenuated dietary‐induced renal functional disorders, abnormal structural remodelling and inflammation. Mechanistically, KLF4 maintained renal mitochondrial biogenesis and activities to combat obesity‐induced mitochondrial dysfunction. In clinical renal biopsies and plasma, the renal Klf4 level was negatively associated with circulating levels of creatinine but positively associated with renal creatinine clearance. In conclusions, the present findings firstly supported that renal KLF4 played an important role in combating obesity‐related nephropathy, and KLF4/mitochondrial function partially determined the energy homeostasis in chronic kidney diseases.     

Biochemical maturation of Spam1 (PH‐20) during epididymal transit of mouse sperm involves modifications of N‐linked oligosaccharides

Indirect immunofluorescence of mouse caput and caudal sperm shows distinctly different distributions of Spam1 protein, which is associated with structural and functional differences of the molecule. Spam1 is uniformly distributed over the surface of the head of caput sperm while in caudal sperm, light and confocal microscopy demonstrate that it is localized to the anterior and posterior regions. The hyaluronidase activity of Spam1 in acrosome‐intact caput sperm was significantly lower (4.3‐fold; P < 0.0001) than that of caudal sperm. The increase in enzymatic activity in caudal sperm is accompanied by a reduction in the molecular weight (MW): in extracts from caput sperm there was a major band at ∼74 kDa and a minor band at ∼67 kDa; while for the cauda there was a major band at ∼67 kDa and minor bands at ∼70 and ∼56 kDa. Additionally, the bands from caput sperm were 4.9 to 7.7‐fold less intense than those from caudal sperm. This decreased affinity for the polyclonal anti‐Spam1 suggests the presence of different surface characteristics of the molecule from the two epididymal regions. Computer analysis of the protein structure from Spam1 cDNA sequence reveals four putative N‐linked glycosylation sites, and enzymatic deglycosylation suggests that all sites are functional. After endoglycosidase activity of extracts from caput and caudal sperm, both show a major band with a MW of ∼56 kDa, the size of the membrane‐anchored polypeptide backbone. Based on the difference in size and intensity of the Spam1 bands and hyaluronidase activities from caput and caudal sperm, the data suggest that the activation of Spam1 during epididymal maturation is regulated by deglycosylation. Mol. Reprod. Dev. 52:196–206, 1999. © 1999 Wiley‐Liss, Inc.     

Longitudinal data reveal ontogenetic changes in the wing morphology of a long‐distance migratory bird

In migratory bird species, juveniles normally have shorter and more rounded wings than adults. The causes of this age‐specific difference in wing morphology, however, are largely unknown. Here, we used longitudinal data collected over 3 years from a Pied Flycatcher Ficedula hypoleuca population to assess whether age‐related differences in wing morphology are a consequence of ontogenetic changes or of selection favouring birds with longer and more pointed wings. Our study provides evidence of ontogenetic changes in wing length and shape, whereby birds grow longer and more pointed wings as they grow older. Age‐dependent variation is likely to be adaptive and may partly explain age differences in spring migration phenology and breeding success.     

Acute treatment with relaxin protects the kidney against ischaemia/reperfusion injury

Although recent preclinical and clinical studies have demonstrated that recombinant human relaxin (rhRLX) may have important therapeutic potential in acute heart failure and chronic kidney diseases, the effects of acute rhRLX administration against renal ischaemia/reperfusion (I/R) injury have never been investigated. Using a rat model of 1‐hr bilateral renal artery occlusion followed by 6‐hr reperfusion, we investigated the effects of rhRLX (5 μg/Kg i.v.) given both at the beginning and after 3 hrs of reperfusion. Acute rhRLX administration attenuated the functional renal injury (increase in serum urea and creatinine), glomerular dysfunction (decrease in creatinine clearance) and tubular dysfunction (increase in urinary excretion of N‐acetyl‐β‐glucosaminidase) evoked by renal I/R. These beneficial effects were accompanied by a significant reduction in local lipid peroxidation, free radical‐induced DNA damage and increase in the expression/activity of the endogenous antioxidant enzymes Mn‐ and CuZn‐superoxide dismutases (SOD). Furthermore, rhRLX administration attenuated the increase in leucocyte activation, as suggested by inhibition of myeloperoxidase activity, intercellular‐adhesion‐molecule‐1 expression, interleukin (IL)‐1β, IL‐18 and tumour necrosis factor‐α production as well as increase in IL‐10 production. Interestingly, the reduced oxidative stress status and neutrophil activation here reported were associated with rhRLX‐induced activation of endothelial nitric oxide synthase and up‐regulation of inducible nitric oxide synthase, possibly secondary to activation of Akt and the extracellular signal‐regulated protein kinase (ERK) 1/2, respectively. Thus, we report herein that rhRLX protects the kidney against I/R injury by a mechanism that involves changes in nitric oxide signalling pathway.     

Age‐dependent changes in response property and morphology of a thermosensory neuron and thermotaxis behavior in Caenorhabditis elegans

Age‐dependent cognitive and behavioral deterioration may arise from defects in different components of the nervous system, including those of neurons, synapses, glial cells, or a combination of them. We find that AFD, the primary thermosensory neuron of Caenorhabditis elegans, in aged animals is characterized by loss of sensory ending integrity, including reduced actin‐based microvilli abundance and aggregation of thermosensory guanylyl cyclases. At the functional level, AFD neurons in aged animals are hypersensitive to high temperatures and show sustained sensory‐evoked calcium dynamics, resulting in a prolonged operating range. At the behavioral level, senescent animals display cryophilic behaviors that remain plastic to acute temperature changes. Excessive cyclase activity of the AFD‐specific guanylyl cyclase, GCY‐8, is associated with developmental defects in AFD sensory ending and cryophilic behavior. Surprisingly, loss of the GCY‐8 cyclase domain reduces these age‐dependent morphological and behavioral changes, while a prolonged AFD operating range still exists in gcy‐8 animals. The lack of apparent correlation between age‐dependent changes in the morphology or stimuli‐evoked response properties of primary sensory neurons and those in related behaviors highlights the importance of quantitative analyses of aging features when interpreting age‐related changes at structural and functional levels. Our work identifies aging hallmarks in AFD receptive ending, temperature‐evoked AFD responses, and experience‐based thermotaxis behavior, which serve as a foundation to further elucidate the neural basis of cognitive aging.     

Chronic kidney disease with comorbid cardiac dysfunction exacerbates cardiac and renal damage

To address the pathophysiological mechanisms underlying chronic kidney disease with comorbid cardiac dysfunction, we investigated renal and cardiac, functional and structural damage when myocardial infarction (MI) was applied in the setting of kidney injury (induced by 5/6 nephrectomy—STNx). STNx or Sham surgery was induced in male Sprague–Dawley rats with MI or Sham surgery performed 4 weeks later. Rats were maintained for a further 8 weeks. Rats (n = 36) were randomized into four groups: Sham+Sham, Sham+MI, STNx+Sham and STNx+MI. Increased renal tubulointerstitial fibrosis (P < 0.01) and kidney injury molecule‐1 expression (P < 0.01) was observed in STNx+MI compared to STNx+Sham animals, while there were no further reductions in renal function. Heart weight was increased in STNx+MI compared to STNx+Sham or Sham+MI animals (P < 0.05), despite no difference in blood pressure. STNx+MI rats demonstrated greater cardiomyocyte cross‐sectional area and increased cardiac interstitial fibrosis compared to either STNx+Sham (P < 0.01) or Sham+MI (P < 0.01) animals which was accompanied by an increase in diastolic dysfunction. These changes were associated with increases in ANP, cTGF and collagen I gene expression and phospho‐p38 MAPK and phospho‐p44/42 MAPK protein expression in the left ventricle. Addition of MI accelerated STNx‐induced structural damage but failed to significantly exacerbate renal dysfunction. These findings highlight the bidirectional response in this model known to occur in cardiorenal syndrome (CRS) and provide a useful model for examining potential therapies for CRS.     

Small RNAs induce the activation of the pro‐inflammatory TLR7 signaling pathway in aged rat kidney

We have recently reported that TLR‐related genes, including TLR7, are upregulated during aging. However, the role of TLR7 and its endogenous ligand in inflammation related to aging is not well defined. Here, we established that small RNAs trigger age‐related renal inflammation via TLR7 signaling pathway. We first investigated the expression changes of nine different TLRs in kidney of 6‐month‐old young rats and 20‐month‐old aged rats. The results revealed that the expression of TLR7 was the highest among nine TLRs in kidney of old rats compared to the young aged rats. Next, to assess the role of cellular RNA as a TLR7 ligand, we treated a renal tubular epithelial cell line with total RNA isolated from the kidney of young and old rats. The results showed that RNA isolated from old rats showed higher expression of TLR7, IL1β, and TNFα compared to that from young rats. Furthermore, RNA isolated from old rats induced IKKα/β/JNK/NF‐κB activation. To identify RNA that activates TLR7, we isolated small and large RNAs from old rat kidney and found that small RNAs increased TLR7 expression in cells. Finally, to investigate the local inflammatory response by small RNA, C57B/L6 mice were intraperitoneally injected with small RNAs isolated from young and old rats; thereby, RNA isolated from old rats induced higher inflammatory responses. Our study demonstrates that renal small RNAs from aged rats induce pro‐inflammatory processes via the activation of the TLR7/IKKα/β/JNK/NF‐κB signaling pathway, and highlights its causative role as a possible therapeutic target in age‐related chronic renal inflammation.     

SFRP1 CpG island methylation locus is associated with renal cell cancer susceptibility and disease recurrence

Loss of the secreted Fzd-related protein 1 (SFRP1) and concurrent alteration of the SFRP1/WNT pathway are frequently observed in human cancers such as in renal cell cancer (RCC). Whether methylation of a SFRP1 CpG island locus in normal human solid tissues is associated with increased tissue specific cancer risk has not been determined to date. Here we measure the cancer risk attributable to SFRP1 DNA methylation in renal tissue. Pyrosequencing of bisulfite treated DNA was used for a case-control study including 120 normal-appearing renal tissues of autopsy specimens and 72 normal-appearing tissues obtained from tumor adjacent areas, and a cross sectional study of 96 RCCs. Association of methylation with demographic risk factor age, clinicopathological parameters and course of patients was investigated. We show significant hypermethylation of a SFRP1 CpG island locus in normal-appearing renal tissues from RCC patients compared with normal-appearing autopsy kidney tissues. Inter quartile analysis revealed a 6-, 13- and 11-fold increased cancer risk for the second, third and fourth quartiles of methylation in the age matched subgroup of tissues (p = 0.001, p = 1.3E-6, p = 6.9E-6). Methylation in autopsy tissues increased with age and methylation in tumors was an independent predictor of recurrence free survival. SFRP1 DNA methylation, accumulates with age in normal-appearing kidney tissues and is associated with increased renal cancer risk, suggesting this CGI sub region as an epigenetic susceptibility locus for RCC. Our data underline the need to further analyze the tissue specific risks conferred by methylated loci for the development of human cancers.     

Increased curvature of hollow fiber membranes could up‐regulate differential functions of renal tubular cell layers

Tissue engineering devices as in vitro cell culture systems in scaffolds has encountered the bottleneck due to their much lower cell functions than real tissues/organs in vivo. Such situation has been improved in some extent by mimicking the cell microenvironments in vivo from either chemical or physical ways. However, microenvironmental curvature, commonly seen in real tissues/organs, has never been manipulated to regulate the cell performance in vitro. In this regard, this paper fabricated polysulfone membranes with or without polyethylene glycol modification to investigate the impact of curvature on two renal tubular cells. Regardless the varying membrane curvatures among hollow fiber membranes of different diameters and flat membrane of zero curvature, both renal cells could well attach at 4 h of seeding and form similar confluent layers at 6 days on each membrane. Nevertheless, the renal cells on hollow fibers, though showing confluent morphology as those on flat membranes, expressed higher renal functions and, moreover, the renal functions significantly increased with the membrane curvature among hollow fibers. Such upregulation on functions was unassociated with mass transport barrier of hollow fibers, because the cultures on lengthwise cut hollow fibers without mass transfer barrier showed same curvature effect on renal functions as whole hollow fibers. It could be proposed that the curvature of hollow fiber membrane approaching to the large curvature in kidney tubules increased the mechanical stress in the renal cells and thus might up‐regulate the renal cell functions. In conclusion, the increase of substrate curvature could up‐regulate the cell functions without altering the confluent cell morphology and this finding will facilitate the design of functional tissue engineering devices. Biotechnol. Bioeng. 2013; 110: 2173–2183. © 2013 Wiley Periodicals, Inc.     

A roadmap for the genetic analysis of renal aging

Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age‐related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age‐associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high‐resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression.     

Synthesis of ultrasmall superparamagnetic iron oxides using reduced polysaccharides

Investigation into the effect of the reducing sugar of dextran on formation and stability of dextran-coated ultrasmall superparamagnetic iron oxides (USPIO) has demonstrated that reduction of the terminal reducing sugar can have a significant effect on particle size, coating stability, and magnetic properties. Four aspects of polysaccharide-coated USPIO particle synthesis were investigated: (i) the effect reduction of the terminal polysaccharide sugar has upon polysaccharide usage, particle size, stability, and magnetic susceptibility; (ii) the effect an exogenous reducing sugar can have upon particle synthesis; (iii) the effect the molecular weight of the reduced polysaccharide has on particle synthesis; and (iv) the effectiveness of reduced and native dextrans in stabilizing a preformed magnetic sol. For low molecular weight dextrans (MW 20,000 x 10(-6) cgs). Similar results were obtained with a 12 kDa pullulan. The effect of polysaccharide molecular weight on particle size was studied, wherein higher molecular weight reduced dextrans produced larger particles. The effectiveness of the reduced and native dextrans in stabilizing a preformed magnetic sol was compared. Reduced dextrans were found to be superior for stabilizing the magnetic sol. The observed effects of reduction of the terminal sugar in dextran compared with the native dextran were modeled using the Langmuir adsorption isotherm. A good fit of experimental data with this model was found.     

Fibroblast growth factor 2 protects against renal ischaemia/reperfusion injury by attenuating mitochondrial damage and proinflammatory signalling

Ischaemia‐reperfusion injury (I/RI) is a common cause of acute kidney injury (AKI). The molecular basis underlying I/RI‐induced renal pathogenesis and measures to prevent or reverse this pathologic process remains to be resolved. Basic fibroblast growth factor (FGF2) is reported to have protective roles of myocardial infarction as well as in several other I/R related disorders. Herein we present evidence that FGF2 exhibits robust protective effect against renal histological and functional damages in a rat I/RI model. FGF2 treatment greatly alleviated I/R‐induced acute renal dysfunction and largely blunted I/R‐induced elevation in serum creatinine and blood urea nitrogen, and also the number of TUNEL‐positive tubular cells in the kidney. Mechanistically, FGF2 substantially ameliorated renal I/RI by mitigating several mitochondria damaging parameters including pro‐apoptotic alteration of Bcl2/Bax expression, caspase‐3 activation, loss of mitochondrial membrane potential and K_ATP channel integrity. Of note, the protective effect of FGF2 was significantly compromised by the K_ATP channel blocker 5‐HD. Interestingly, I/RI alone resulted in mild activation of FGFR, whereas FGF2 treatment led to more robust receptor activation. More significantly, post‐I/RI administration of FGF2 also exhibited robust protection against I/RI by reducing cell apoptosis, inhibiting the release of damage‐associated molecular pattern molecule HMBG1 and activation of its downstream inflammatory cytokines such as IL‐1α, IL‐6 and TNF α. Taken together, our data suggest that FGF2 offers effective protection against I/RI and improves animal survival by attenuating mitochondrial damage and HMGB1‐mediated inflammatory response. Therefore, FGF2 has the potential to be used for the prevention and treatment of I/RI‐induced AKI.