Biomedical subjects

Yashpal S Kanwar

Publications and source records attributed to Yashpal S Kanwar.

At least 19 recordsLinked to original sources

PubMed2006

ZHX proteins regulate podocyte gene expression during the development of nephrotic syndrome.

Transcriptional regulation of podocyte gene expression in primary glomerular disease is poorly understood. In this study, we demonstrate a prominent role of members of the ZHX (zinc fingers and homeoboxes) family of proteins in regulating podocyte gene expression during the development of nephrotic syndrome. While studying mechanisms of glomerular disease, rat ZHX3 was cloned from a down-regulated gene fragment; its cellular localization, DNA binding, and transcriptional repressor properties were characterized; and its ability to influence podocyte gene expression directly or via ZHX1 and ZHX2 was studied. In eukaryotic promoters, ZHX3 bound to the CdxA binding motif. ZHX proteins were mostly sequestered in the non-nuclear compartment in the normal in vivo podocyte by virtue of heterodimer formation, and loss of heterodimerization was associated with entry into the nucleus. In experimental minimal change disease, ZHX3 was transiently down-regulated prior to the onset of proteinuria, and recovery of expression was associated with migration of ZHX3 protein into the nucleus and the development of proteinuria. This expression pattern mirrored the increased nuclear ZHX3 expression noted in vivo in the podocytes in human minimal change disease biopsies. In vitro, migration of ZHX3 protein into the nucleus during recovery from transient ZHX3 knockdown reproduced the gene expression profile of in vivo minimal change disease. Severe sustained knockdown of ZHX3 caused down-regulation of genes involved in focal sclerosis, including WT1, mediated mostly by increased nuclear entry of ZHX2 and ZHX1. In summary, ZHX proteins are major transcriptional mediators of podocyte disease.

Animals↗

PubMed2006

Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice.

For investigation of how the vascular endothelial growth factor (VEGF) system participates in the pathogenesis of diabetic kidney disease, type 2 diabetic db/db and control db/m mice were treated intraperitoneally with vehicle or 2 mg/kg of a pan-VEGF receptor tyrosine kinase inhibitor, SU5416, twice a week for 8 wk. Efficacy of SU5416 treatment in the kidney was verified by the inhibition of VEGF receptor-1 phosphorylation. Glomerular VEGF immunostaining, normally increased in diabetes, was unaffected by SU5416. Plasma creatinine did not change with diabetes or SU5416 treatment. The primary end point of albuminuria increased approximately four-fold in the diabetic db/db mice but was significantly ameliorated by SU5416. Correlates of albuminuria were investigated. Diabetic glomerular basement membrane thickening was prevented in the SU5416-treated db/db mice, whereas mesangial matrix expansion remained unchanged by treatment. The density of open slit pores between podocyte foot processes was decreased in db/db diabetes but was partly increased toward normal by SU5416. Finally, nephrin protein by immunofluorescence was decreased in the db/db mice but was significantly restored by SU5416. Paradoxically, total nephrin protein by immunoblotting was increased in diabetes, pointing toward a possible dysregulation of nephrin trafficking. Diabetic albuminuria is partially a function of VEGF receptor signaling overactivity. VEGF signaling was found to affect a number of podocyte-driven manifestations such as GBM thickening, slit pore density, and nephrin quantity, all of which are associated with the extent of diabetic albuminuria. By impeding these pathophysiologic processes, VEGF receptor inhibition by SU5416 might become a useful adjunct to anti-albuminuria therapy in diabetic nephropathy.

Albuminuria↗

PubMed2006

HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced "inside-out" signaling to extracellular matrix by preventing RhoA activation.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert modulatory effects on a number of cell signaling cascades by preventing the synthesis of various isoprenoids derived from the mevalonate pathway. In the present study, we describe a novel pleiotropic effect of HMG-CoA reductase inhibitors, also commonly known as statins, on vascular endothelial growth factor (VEGF)-induced type IV collagen accumulation. VEGF is an angiogenic polypeptide that is also known to play a central role in endothelial cell permeability and differentiation. Recently, VEGF has also been implicated in promoting extracellular matrix (ECM) accumulation, although the precise signaling mechanism that mediates VEGF-induced ECM expansion remains poorly characterized. Elucidation of the mechanisms through which VEGF exerts its effect on ECM is clearly a prerequisite for both understanding the complex biology of this molecule as well as targeting VEGF in several pathological processes. To this end, this study explored the underlying molecular mechanisms mediating VEGF-induced ECM expansion in mesangial cells. Our findings show that VEGF stimulation elicits a robust increase in ECM accumulation that involves RhoA activation, an intact actin cytoskeleton, and beta(1)- integrin activation. Our data also indicate that simvastatin, via mevalonate depletion, reverses VEGF-induced ECM accumulation by preventing RhoA activation.

Actin Cytoskeleton↗

PubMed2006

Therapeutic approach for diabetic nephropathy using gene delivery of translocase of inner mitochondrial membrane 44 by reducing mitochondrial superoxide production.

Hyperglycemia-induced overproduction of mitochondrial reactive oxygen species has emerged as a major player in diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane 44 (TIM44) was identified by upregulation in diabetic mouse kidneys. TIM44 functions as a membrane anchor of mitochondrial heat-shock protein 70 (mtHsp70) to TIM23 complex and is involved in the import of mitochondria-targeted preproteins into mitochondrial matrix. The process is dependent on inner membrane potential and ATP hydrolysis on ATPase domain of mitochondrial heat-shock protein 70. Hemagglutination virus of Japan-envelope vector that carries pcDNA3.1 plasmid that contains the full-length cDNA of TIM44 and control plasmid were injected weekly into the tail vein of uninephrectomized streptozotocin-induced diabetic CD-1 mice. The gene delivery alleviated proteinuria and renal hypertrophy at 8 wk after the injection, inhibited renal cell proliferation and apoptosis, and suppressed superoxide production. In vitro experiments, using human proximal tubular (HK2) cells, revealed that the gene delivery of TIM44 reversed high glucose-induced metabolic and cellular abnormalities such as enhanced reactive oxygen species production, increased ATP contents, alterations in inner membrane potential, increased cell proliferation, and apoptosis. Transfection with siRNA and expressing vector of TIM44 revealed that TIM44 facilitates import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase into mitochondria. The gene delivery of TIM44 therefore seems to be beneficial for the maintenance of mitochondrial function and is a novel therapeutic approach for diabetic nephropathy.

Adenosine Triphosphate↗

PubMed2006

Expression and potential role of dentin phosphophoryn (DPP) in mouse embryonic tissues involved in epithelial-mesenchymal interactions and branching morphogenesis.

Dentin sialophosphoprotein (DSPP) is synthesized in both mesenchyme and epithelium at varying stages of tooth development. At the tooth cap stage, corresponding to embryonic day (E) 13.5 of mouse embryonic life, the phosphophoryn (DPP) portion of DSPP was immunohistochemically localized to the enamel organ with intense staining of oral ectoderm but no expression in dental follicle mesenchyme. Surprisingly, DPP was also expressed in ureteric bud branches of embryonic metanephric kidney and alveolar epithelial buds of developing lung. Reverse transcriptase-polymerase chain reaction analysis verified the presence of DSPP mRNA with identical sequences in the tooth, lung, and kidney. The DSPP(-/-) mouse with ablated DPP expression in the teeth, also exhibited aberrant organogenesis in kidney and lung. In the kidney, malformed metanephric S-shaped bodies and increased mesenchymal apoptosis were observed. Inclusion of anti-DPP antibodies in organ culture of metanephroi, harvested from E13.5 wild-type mice, likewise resulted in altered ureteric bud morphogenesis, suggesting a role for DPP in epithelial-mesenchymal interactions in meristic tissues during embryonic development.

Animals↗

PubMed2006

Expression and functional characteristics of tubular transporters: P-glycoprotein, PEPT1, and PEPT2 in renal mass reduction and diabetes.

Renal mass reduction is associated with a compromise in renal excretion, and thus dosages of drugs need to be adjusted to avoid adverse reactions and to ensure their effectiveness. A prototypic example is patients who had undergone transplantation due to a variety of causes, including diabetic nephropathy; the latter appears to be the major cause of renal failure requiring hemodialysis and transplantation. Conceivably, hyperglycemia with reduced renal mass interferes in the delivery of xenobiotics handled by various tubular transporters. In this investigation, effect of renal mass reduction/hyperglycemia on gene and protein expression of P-glycoprotein (Pgp), PEPT1, and PEPT2 was assessed. Also, [H(3)]glycylsarcosine uptake, a prototype of dipeptide, was measured in various groups of rats: sham-operated, uninephrectomized, streptozotocin-induced diabetes, and diabetic + uninephrectomized. An increase in Pgp, PEPT1, and PEPT2 expression was observed in kidneys of uninephrectomy rats, the highest being in the Pgp. Similarly, an increase was observed in diabetic rats who had undergone uninephrectomy, although less than those with nephrectomy alone. No differences were observed between sham-operated and diabetic groups. Increased uptake of [H(3)]glycylsarcosine was also seen in uninephrectomised rats. A modest uptake was observed in diabetic rats who had undergone uninephrectomy. The data suggest that uninephrectomy induces an increase in the expression and activity of transporters localized to renal tubular epithelial brush border. The fact that upregulation and activity of the peptide transporters were less in kidneys of diabetic animals who had undergone uninephrectomy compared with uninephrectomy alone suggests that hyperglycemia interferes in their expression and activity during the compensatory phase.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience.

Biological properties of renal-specific oxidoreductase (RSOR), characteristics of its promoter, and underlying mechanisms regulating its expression in diabetes were analyzed. RSOR expression, normally confined to the renal cortex, was markedly increased and extended into the outer medullary tubules in db/db mice, a model of type 2 diabetes. Exposure of LLCPK cells to d-glucose resulted in a dose-dependent increase in RSOR expression and its enzymatic activity. The latter was related to one of the glycolytic enzymes, myo-inositol oxygenase. The increase in activity was in proportion to serum glucose concentration. The RSOR expression also increased in cells treated with various organic osmolytes, e.g., sorbitol, myoinositol, and glycerolphosphoryl-choline and H(2)O(2). Basal promoter activity was confined to -1,252 bp upstream of ATG, and it increased with the treatment of high glucose and osmolytes. EMSAs indicated an increased binding activity with osmotic-, carbohydrate-, and oxidant-response elements in cells treated with high glucose and was abolished by competitors. Supershifts, detected by anti-nuclear factor of activated T cells, and carbohydrate-response-element-binding protein established the binding specificity. Nuclear factor of activated T cells tonicity-enhancer-binding protein and carbohydrate-response-element-binding protein had increased nuclear expression in cells treated with high glucose. The activity of osmotic-response element exhibited a unique alternate binding pattern, as yet unreported in osmoregulatory genes. Data indicate that RSOR activity is modulated by diverse mechanisms, and it is endowed with dual properties to channel glucose intermediaries, characteristic of hepatic aldehyde reductases, and to maintain osmoregulation, a function of renal medullary genes, e.g., aldose reductase, in diabetes.

Animals↗

PubMed2005

Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms.

Galectins are beta-galactoside-binding lectins that are involved in various biologic processes, such as apoptosis, cell proliferation, and cell-cycle regulation. Galectin-9 (Gal-9) was identified previously and demonstrated to have apoptotic potential to thymocytes in mice and activated CD8(+) T cells in nephrotoxic serum nephritis model. In this study, the effect of Gal-9 on G1-phase cell-cycle arrest, one of the hallmark pathologic changes in early diabetic nephropathy, was investigated. Eight-week-old male db/db mice received injections of recombinant Gal-9 or vehicle for 8 wk. The injection of Gal-9 into db/db mice significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion. Gal-9 reduced glomerular expression of TGF-beta1 and the number of p27(Kip1)- and p21(Cip1)-positive cells in glomeruli. Double staining with nephrin and type IV collagen revealed that podocytes were mainly positive for p27(Kip1). For further confirming the cell-cycle regulation by Gal-9, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 mM d-glucose supplemented with Gal-9. Cell-cycle distribution analyses revealed that Gal-9 maintained further progression of cell cycle from the G1 phase. Gal-9 reversed the high-glucose-mediated upregulation of p27(Kip1) and p21(Cip1) and inhibited cell-cycle-dependent hypertrophy, i.e., reduced [(3)H]proline incorporation. The data suggest that Gal-9 plays a central role in inducing their successful progression from G1 to G2 phase by suppressing glomerular expression of TGF-beta1 and inhibition of cyclin-dependent kinase inhibitors. Gal-9 may give an impetus to develop new therapeutic tools targeted toward diabetic nephropathy.

Animals↗

PubMed2005

HMG CoA reductase inhibition modulates VEGF-induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation.

The beneficial effects of statins are usually assumed to stem from their ability to reduce cholesterol biosynthesis. However, because statins are potent inhibitors of the mevalonate, which governs diverse cell signaling pathways, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase may also result in pleiotropic effects. The present study describes a novel pleiotropic effect of statins on vascular endothelial growth factor (VEGF)-induced glomerular endothelial cell (GEnC) hyperpermeability. Using live cell imaging with green fluorescent protein-tagged myosin regulatory light chain (MLC) and correlative biochemical analyses, we investigated 1) VEGF signaling pathway leading to GEnC hyperpermeability and 2) the modulatory effects of statins on VEGF signaling. Our findings indicate that VEGF stimulation elicits a robust increase in GEnC permeability. The signaling pathway that mediates VEGF-induced GEnC hyperpermeability involves RhoA activation leading to actin cytoskeletal remodeling, MLC diphosphorylation, and enhanced paracellular gap formation. Remarkably, cotreatment of endothelial cells with simvastatin, a hydrophobic statin, reversed VEGF-induced GEnC hyperpermeability by preventing MLC diphosphorylation, and cytoskeletal remodeling. In summary, this study identifies RhoA and MLC phosphorylation as key mediators of VEGF-induced endothelial cell hyperpermeability and demonstrates the modulatory effects of statins on VEGF signaling pathway.

Actins↗

PubMed2005

Cell biology of diabetic kidney disease.

In large part cellular dysfunctions induced by chronic hyperglycemia are similar in type-1 and -2 diabetes. In both instances chronic hyperglycemia induces injury to a multitude of organs by affecting various target cells. The cells affected may include those derived from of epithelial or mesenchymal progenitors; and at times hyperglycemia may induce phenotypic changes with epithelial-mesenchymal transformation. In the majority of target cells the high-glucose ambience activates various intracellular pathways that are similar except for minor exceptions that are related to the selective expression of various molecules in a given cell type. Keeping in perspective a common paradigm applicable to most of the cells, a brief discussion of different hyperglycemia-induced cellular events pertaining to various pathways is described in this review. They include fluxes of glucose intermediaries in various cellular metabolic pathways, generation of advanced glycation end products (AGEs) and their extra- and intracellular effects, the role of protein kinase C, transforming growth factor-beta, guanosine triphosphate-binding proteins and reactive oxygen species (ROS) in various cellular signaling events. The latter, i.e., ROS, may be central to several intracellular pathways and modulate various events in a reciprocal manner. The information compiled under various subtitles of this synopsis is derived from an enormous amount of literature data summarized in several recent excellent reviews, and thus further reading of them is suggested to gather detailed comprehensive information on each of the subjects.

Animals↗

PubMed2005

Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity.

There is a rapid global rise in obesity, and the link between obesity and diabetes remains somewhat obscure. We identified an adipocytokine, designated as visceral adipose tissue-derived serpin (vaspin), which is a member of serine protease inhibitor family. Vaspin cDNA was isolated by from visceral white adipose tissues (WATs) of Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model of abdominal obesity with type 2 diabetes. Rat, mouse, and human vaspins are made up of 392, 394, and 395 amino acids, respectively; exhibit approximately 40% homology with alpha1-antitrypsin; and are related to serine protease inhibitor family. Vaspin was barely detectable in rats at 6 wk and was highly expressed in adipocytes of visceral WATs at 30 wk, the age when obesity, body weight, and insulin levels peak in OLETF rats. The tissue expression of vaspin and its serum levels decrease with worsening of diabetes and body weight loss at 50 wk. The expression and serum levels were normalized with the treatment of insulin or insulin-sensitizing agent, pioglitazone, in OLETF rats. Administration of vaspin to obese CRL:CD-1 (ICR) (ICR) mice fed with high-fat high-sucrose chow improved glucose tolerance and insulin sensitivity reflected by normalized serum glucose levels. It also led to the reversal of altered expression of genes relevant to insulin resistance, e.g., leptin, resistin, TNFalpha, glucose transporter-4, and adiponectin. In DNA chip analyses, vaspin treatment resulted in the reversal of expression in approximately 50% of the high-fat high-sucrose-induced genes in WATs. These findings indicate that vaspin exerts an insulin-sensitizing effect targeted toward WATs in states of obesity.

Adipocytes↗

PubMed2005

Hyperglycemia: its imminent effects on mammalian nephrogenesis.

A sustained exposure of the mammalian embryo to very high glucose ambience is associated with a multitude of congenital birth defects, including those of the cardiovascular, CNS, skeletal and urogenital systems during the first 6-8 weeks of gestation in humans. These urogenital abnormalities may be associated with "caudal regression syndrome" or may occur alone in the form of partial or total renal agenesis. Similarly, an increase in the incidence of morphogenetic defects is observed in the offspring of streptozotocin-induced diabetic rats and mice, and also in non-obese diabetic mice. In certain cases, failure during the growth of the lower parts of embryos or newborn mice involving the genitourinary system has been observed in animals with severe diabetes. Investigators have utilized whole organ culture systems to delineate the mechanisms relevant to dysmorphogenesis of the embryonic metanephros. A marked dysmorphogenesis of the metanephros is observed upon treatment with a high concentration of D: -glucose. Associated with it are changes that include branching dysmorphogenesis of the ureteric bud iterations, reduced population of nascent nephrons, decreased expression of basement membrane proteoglycans, depletion of ATP stores, and fulminant apoptosis of the cells at the interface of mesenchyme and ureteric bud epithelium. The latter findings suggest that disruption of epithelial:mesenchymal interactions may be the major event responsible for the metanephric dysmorphogenesis induced by high glucose ambience.

Animals↗

PubMed2005

Catheter-directed MR angiography and cross-sectional imaging for the assessment of renal artery stenosis.

PURPOSE: Catheter-directed intraarterial (IA) gadolinium (Gd)-enhanced gradient-echo (GRE) imaging has been used in the setting of magnetic resonance (MR) imaging-guided endovascular procedures for two-dimensional (2D) or three-dimensional (3D) depiction of blood vessels. In a swine model, the hypothesis was tested that the combination of 2D IA GRE and 2D cross-sectional steady-state free precession (SSFP) imaging improves assessment of renal artery stenosis (RAS) compared with 3D IA GRE imaging alone. MATERIALS AND METHODS: Bilateral RAS was surgically induced in seven pigs. Detection of stenoses was then compared between the combination of 2D projection IA GRE and cross-sectional 2D SSFP imaging without contrast agent and 3D IA GRE alone. Radiographic digital subtraction angiography (DSA) was employed as the reference standard. Linear regression was used to compare stenosis measurements, with an alpha of 0.05. RESULTS: Radiographic DSA and MR imaging were successful in the seven animals (14 stenoses). With use of linear regression analysis, the combination of 2D IA GRE and 2D SSFP imaging had a higher r(2) (0.87 vs 0.72) and a slope closer to unity (1.02 vs 0.77) compared with 3D IA GRE imaging alone. When comparing intercepts, the regression line for SSFP significantly differed from that of 3D IA GRE imaging (P < .05). CONCLUSION: The combination of 2D IA GRE and cross-sectional 2D SSFP imaging improves the accuracy of RAS detection compared with IA 3D IA-GRE alone.

Anatomy, Cross-Sectional↗

PubMed2005

Renal-specific oxidoreductase biphasic expression under high glucose ambience during fetal versus neonatal development.

BACKGROUND: Renal-specific oxidoreductase (RSOR) has been recently identified in mice kidneys of diabetic animals, and it is developmentally regulated. Its expression during fetal, neonatal, and postnatal periods was assessed under high glucose ambience. METHODS: Whole-mount immunofluorescence and confocal microscopy were performed to assess the effect of high glucose on the morphogenesis of mice fetal kidneys. RSOR mRNA and protein expression was assessed by competitive polymerase chain reaction (PCR) and immunoprecipitation methods in embryonic kidneys (day E13 to E17) subjected to high glucose ambience and by Northern and Western blot analyses of kidneys of newborn and 1-week-old mice with hyperglycemia. The spatiotemporal changes in the RSOR expression were assessed by in situ hybridization analyses and immunofluorescence microscopy. In addition, the extent of apoptosis in the kidneys was determined by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) assay. RESULTS: Whole-mount microscopy of the embryonic metanephroi revealed a dose-dependent disruption in the ureteric bud iterations with reduced population of the nascent nephrons. Both gene and protein expressions were reduced in day E13 to E17 metanephroi, while increased in kidneys of newborn and 1-week-old mice. In day E13 and day E15 kidneys, the RSOR was expressed in the ureteric bud branches and some of the immature tubules, and its expression was reduced with high glucose treatment. In day E17 kidneys the RSOR was expressed in the tubules of the deeper cortex, and its expression was marginally decreased. In newborn kidneys, this enzyme was expressed in the subcortical tubules and it spread to the entire width of the renal cortex in hyperglycemic state. In 1-week-old mice kidneys, the RSOR was localized to the entire cortex, and in animals with blood glucose above 300 mg/dL, its intensity increased with extension of expression into the outer medullary tubules. A dose-dependent fulminant apoptosis was observed in day E13 to E17 kidneys subjected to high glucose ambience. In newborn and 1-week-old mice control kidneys, the apoptosis was minimal although slightly increased during hyperglycemia. CONCLUSION: High glucose has a differential effect on the RSOR expression in kidneys during the embryonic versus neonatal/postnatal period. This may partly be related to the differential degree of apoptosis, a process reflective of oxidant stress that is seen in diabetic milieu, which as previously has been shown to adversely effect the modulators of fetal development and thereby the morphogenesis of the kidney and RSOR expression.

Animals↗

PubMed2005

Gene delivery of Tim44 reduces mitochondrial superoxide production and ameliorates neointimal proliferation of injured carotid artery in diabetic rats.

Hyperglycemia induces the production of reactive oxygen species (ROS) from mitochondria, which is closely related to diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane (Tim)44 was identified by upregulation in streptozotocin (STZ)-induced diabetic mouse kidneys; Tim44 functions as a membrane anchor of mtHsp70 to TIM23 complex and is involved in the import of preproteins with mitochondria-targeted presequence into mitochondrial matrix. The process is dependent on inner membrane potential (Delta psi) and ATP hydrolysis on ATPase domain of mtHsp70. Here, we show that the gene delivery of Tim44 using pcDNA3.1 vector (pcDNA3.1/TIM44) into the balloon injury model of STZ-induced diabetic rats ameliorated neointimal proliferation. ROS production, inflammatory responses, and cell proliferation in injured carotid artery were diminished by delivery of pcDNA3.1/TIM44. In vitro experiments using human aortic smooth muscle cells (HASMCs) revealed that the gene delivery of Tim44 normalized high-glucose-induced enhanced ROS production and increased ATP production, alterations in inner membrane potential, and cell proliferation. Transfection of siRNA and pcDNA3.1/TIM44 using HASMC culture clarified that import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase was facilitated by Tim44. Tim44 and its related molecules in mitochondrial import machinery complex are novel targets in the therapeutic interventions for diabetes and its vascular complications.

Adenosine Triphosphate↗

PubMed2004

Matrix metalloproteinases in renal development.

Matrix metalloproteinases (MMPs) are enzymes with metal ion-dependent activity that degrade extracellular matrix (ECM) glycoproteins. MMPs play a vital role in various biological processes, such as embryogenesis, tissue remodeling, angiogenesis, and wound healing, and in certain disease processes, for example, metastasis of cancer cells. Following their activation, MMPs are believed to modulate both cell-cell and cell-matrix interactions, which in turn regulate cellular differentiation, migration, proliferation, and cell survival. Being involved in pericellular proteolysis, they maintain a gradient of ECM proteins by balancing ECM synthesis and degradation. Such a balance is critical for various mammalian developmental processes during embryonic life and also for the homeostasis of various organs and reparative processes in later life. During the past two decades the role of MMPs in the morphogenesis of various organs, including that of the metanephros, has been investigated extensively. Mammalian nephrogenesis comprises a series of intricate events characterized by a sustained remodeling and turnover of ECM, suggesting a potential role of MMPs in renal development. Conceivably, reciprocal inductive epithelial-mesenchymal interactions that take place at the very commencement of nephrogenesis are modulated by a number of ECM proteins. Their expression, especially at the epithelial-mesenchymal interface, are critical for metanephric development, and such a strategic expression is likely to be modified by a number of different macromolecules that exhibit spatiotemporal and stage-specific expression. Among them the most suitable candidate that could exert such a control would be MMPs. This review addresses the current status of our understanding of the functions and the role of MMPs in renal development.

Animals↗

PubMed2004

Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy.

3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitors or statins are competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis. Several large landmark clinical studies have shown a marked reduction of cardiovascular mortality and morbidity in patients treated with statins. Because of the strong association between serum cholesterol levels and coronary artery disease, investigators initially assumed that the predominant beneficial effects of statins result from their lipid-lowering properties. However, more recent observations have suggested that the clinical benefits of statins may be in part independent of their cholesterol-lowering effects. The pleiotropic or cholesterol-independent effects of statins might result from preventing the production of isoprenoids. Isoprenoids serve as important lipid attachments for the post-translational modification of a variety of proteins such as small GTP binding proteins implicated in intracellular signaling. The list of different pleiotropic effects of statins is still growing and, among others, includes the modulatory effects of statins on endothelial function, oxidative stress, coagulation, plaque stability, and inflammation. The pleiotropic effects of statins represent an area of great interest in prevention and therapy of cardiovascular and other chronic diseases. An area of particular interest is the potential beneficial effects of statins in diabetes and its micro/macrovascular complications. This review summarizes our current understanding of the pleiotropic effects of statins in diabetes and the modulatory effects of statins in various pathobiological pathways involved in diabetes and its complications.

Animals↗

PubMed2004

Simvastatin modulates angiotensin II signaling pathway by preventing Rac1-mediated upregulation of p27.

Recent experimental observations have suggested that statins may exert modulatory effects on a number of pathobiological processes beyond their cholesterol-lowering properties. Some of the pleiotropic effects of statins seem to be mediated by their ability to block the synthesis of isoprenoid intermediates, which serve as important lipid attachments required for the proper function and activation of the small GTP-binding proteins. The current study explored the modulatory effects of simvastatin (SMV) on the angiotensin II (Ang II)-induced Rac1-mediated, upregulation of cyclin-dependent kinase inhibitor p27. Ang II (100 nM) stimulation of rat mesangial cells induced a significant increase in p27 protein expression. Co-treatment of cells with SMV (1 microM) inhibited Ang II-induced upregulation of p27 protein. Addition of mevalonate (200 microM) or geranylgeranyl pyrophosphate (5 microM) reversed the inhibitory effect of SMV on p27 protein expression, suggesting that the effect of SMV is geranylgeranyl dependent. This study also provides evidence for a sequential link between Ang II stimulation and downstream activation of Rac1, intracellular H2O2 production, and Akt kinase leading to upregulation of p27 protein in mesangial cells. It was also shown that SMV, by inhibiting Rac1 activity, reversed Ang II-induced increase in intracellular H2O2 production, Akt activation, and p27 protein expression. The data presented in this study not only elucidate Ang II-mediated signaling cascade in mesangial cells but also demonstrate for the first time the modulatory effects of SMV on Ang II-induced signaling pathway at the cell cycle level.

Active Transport, Cell Nucleus↗