Biomedical subjects

G Wolf

Publications and source records attributed to G Wolf.

At least 163 records · Page 9Linked to original sources

PubMed1999

The effect of the immunosuppressant FK 506 on peripheral nerve regeneration following nerve grafting.

Nerve allografts are highly antigenic and require the continuous use of immunosuppressive drugs. Neurotoxic complications from immunosuppressant therapy with FK 506 have been noted in the central and peripheral nervous system although an increased rate of axonal regeneration has also been noted. Regeneration of peripheral nerve grafts was assessed in a rat model clinically and morphometrically after treatment for 2 and 6 weeks with two different doses of FK 506. Good regeneration was noted in all groups at 6 weeks. A significantly higher axon count was observed in both the FK 506 groups after 2 weeks regeneration compared with controls. This beneficial effect was not evident after 6 weeks of regeneration. Whether this is related to a pruning mechanism or to a down-regulation of regenerative processes in the nerve due to possible neurotoxic effects of FK 506 remains unknown.

Animals↗

PubMed1999

Hyperuricemia and renal insufficiency associated with malignant disease: urate oxidase as an efficient therapy?

Hyperuricemia is a common finding in patients with malignant diseases. Chemotherapy can induce life-threatening tumor lysis syndrome with severe hyperuricemia, other metabolic abnormalities, and acute renal failure. Intrarenal precipitation of uric acid contributes to renal insufficiency in this situation. Allopurinol, by preventing the conversion of hypoxanthine and xanthine to uric acid, has been long considered the standard pharmacological approach to hyperuricemia and prevention of tumor lysis syndrome. However, allopurinol itself may facilitate precipitation of xanthine crystals and has little influence on already-formed uric acid crystals deposited in the kidney. Urate oxidase further oxidizes uric acid to the highly water-soluble allantoin in mammals, except humans, who lack this enzyme. We report four cases of hyperuricemia (initial serum uric acid concentrations, 14.0 to 25.0 mg/dL) associated with malignant diseases treated with exogenous urate oxidase. Two of the patients showed full-blown tumor lysis syndrome. A single urate oxidase infusion (1,000 U) readily reduced serum uric acid levels in all patients. Furthermore, renal insufficiency, determined by serum creatinine concentrations, improved in three of the four patients. No adverse effects were observed. Currently, a recombinant urate oxidase is undergoing clinical testing and may make this efficient therapy more widely available. We believe that treatment with urate oxidase is a safe and efficient therapy for patients with cancer-associated hyperuricemia and may be effective even in individuals with only moderately elevated serum uric acid concentrations.

Journal Article↗

PubMed1999

Effect of arginine on basal and high potassium-induced efflux of [3H]D-aspartate from rat striatal slices.

There are conflicting reports in the literature regarding the effects of nitric oxide as well as the involvement of the cyclic GMP pathway on the transmitter release. To study the influence of the availability of the nitric oxide precursor arginine on the glutamate transmission process, rat striatal slices preloaded with the tritiated glutamate analogue D-aspartate were used. L-Arginine stimulated in a concentration-dependent way (0.01-10.0 mM) the high potassium-induced efflux of [3H]D-aspartate. The basal release was increased only by 10 mM L-arginine. Neither the basal nor the depolarization-induced efflux of [3H]D-aspartate was affected by D-arginine. The L-arginine effect was abolished by the nitric oxide synthase inhibitor L-arginine methyl ester and was not modified by cyclic GMP. Only at high concentrations of L-arginine (10 mM) could an elevation of cyclic GMP level be demonstrated. The results are discussed in terms of direct presynaptic action of nitric oxide on [3H]D-aspartate efflux and a possible modulation of glutamate release by the availability of arginine.

Animals↗

PubMed1999

Selective targeting of somatostatin receptor 3 to neuronal cilia.

Recently, five members of the somatostatin receptor family have been cloned. However, little is known about their cellular and subcellular localization in the central nervous system. Using specific anti-peptide antisera, we observed somatostatin receptor 3-like immunoreactivity in many brain regions, including the cerebral cortex, hippocampus, hypothalamus, amygdala and cerebellum. In all of these regions (except for the cerebellar cortex), somatostatin receptor 3-like immunoreactivity was selectively targeted to 4-8-microm-long rod-shaped profiles which did not co-localize with axonal or dendritic markers. One immunoreactive profile was always associated with one neuronal cell body. This staining pattern was resistant to colchicine treatment and showed a closely overlapping distribution with somatostatin receptor 3 messenger RNA, suggesting that the receptor protein is not transported over long distances. Electron microscopic analysis revealed that somatostatin receptor 3-like immunoreactivity is localized to the plasma membrane of neuronal cilia which extended into an intercellular pocket and showed a 9+0 filament pattern in their basal body and proximal segments. Thus, somatostatin receptor 3 demonstrates a unique example of a G-protein-coupled receptor not localized to "classical" pre- or postsynaptic sites, but selectively targeted to neuronal cilia. The presence of the somatostatin receptor 3 receptor on neuronal cilia suggests that these presumably non-motile cilia may not merely represent developmental remnants, but rather function as chemical sensors of the immediate milieu.

Amino Acid Sequence↗

PubMed1999

Ultrastructural localization of neuronal nitric oxide synthase in the laterodorsal tegmental nucleus of wild-type and knockout mice.

The cellular and subcellular distribution of neuronal nitric oxide synthase and its related reduced beta-nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase activity was compared in wild-type and homozygous knockout mice, in which the gene for neuronal nitric oxide synthase has been disrupted, resulting in a lack of the predominant splice isoform alpha. In the laterodorsal tegmental nucleus, used as a model structure, the cholinergic principal neurons also exhibited an intensive neuronal nitric oxide synthase immunoreactivity. Using the tetrazolium salt 2-(2-benzothiazolyl)-5-styryl-3-(4'-phthalhydrazidyl)-tetrazo++ +-lium chloride (BSPT), these neurons were filled with NADPH-diaphorase reaction product, whereas the equivalent neurons of knockout mice showed, if at all, only traces of neuronal nitric oxide synthase immunoreactivity in parallel to a diminished NADPH-diaphorase labelling. Subcellularly, the neuronal nitric oxide synthase-related diaminobenzidine product was, apparently owing to diffusion artifact, more or less evenly distributed in the cytosol of the neuronal perikarya and dendrites of wild-type mice. In contrast, the BSPT reaction product formazan was closely and discretely attached to endocellular membranes. In the intensely NADPH-diaphorase stained neurons of wild-type mice, 85% of the mitochondria were, at least partly, labelled for BSPT-formazan, whilst in the equivalent neurons of mutant mice, only 13% of mitochondria were NADPH-diaphorase positive. Related to the NADPH-diaphorase activity in the principal neurons of wild-type mice, only 10% of membranes of the endoplasmic reticulum, 27% of mitochondrial membranes and 26% of the nuclear envelope exhibited NADPH-diaphorase activity in the mutant mice. Our findings with the BSPT histochemistry suggest that residues of NADPH-diaphorase positivity in mutant mice are attributed to the alternative splice isoforms beta and/or gamma of neuronal nitric oxide synthase. The splice isoform a is located predominantly at the membranes of the endoplasmic reticulum.

Animals↗

PubMed1999

The function of cholesterol in embryogenesis.

Cholesterol is critical in embryonic development. Inhibition of cholesterol synthesis in experimental animals has caused a birth defect called holoprosencephaly (HPE), which is evidenced by cyclopia (one eye in the middle of the face), monorhinia (protruding single nose above the eye), absence of the pituitary gland, and central nervous system (CNS) abnormalities. In humans, an inherited defect in the cholesterol-synthesizing enzyme 7-dehydrocholesterol reductase depletes cholesterol and results in human HPE, termed Smith-Lemli-Opitz syndrome. In its most severe form, the syndrome leads to cyclopia, monorhinia, and lack of separation of cerebral hemispheres. The cause of the syndrome is a defect in a protein coded by the gene Sonic hedgehog (SHH). The protein SHH is expressed in the notochord of the CNS in the early embryo and is activated by being cleaved autocatalytically, with simultaneous covalent attachment of cholesterol to the N-terminal fragment, which is secreted by cells of the mesoderm layer, signaling the establishment of the neural midline cells. Thus, cholesterol is essential for proper signaling in the development of the normal embryo.

Journal Article↗

PubMed1999

Photodynamic effects induced by meso-tetrakis[4-(carboxymethyleneoxy)phenyl] porphyrin on isolated Sarcoma 180 ascites mitochondria.

Using mitochondria isolated from Sarcoma 180 ascites tumour in Swiss mice as a model system, we have evaluated the ability of a novel porphyrin, meso-tetrakis[4-(carboxymethyleneoxy)phenyl]porphyrin (H2T4CPP), to induce damage on photosensitization. Oxidative damage to mitochondria, one of the primary and crucial targets of the photodynamic effect, is assessed by measuring products of lipid peroxidation such as thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (LOOH), besides the loss of activity of the mitochondrial marker enzyme succinate dehydrogenase (SDH). Analysis of product formation, the effect of deuteration and selective inhibition by scavengers of reactive oxygen species (ROS) show that the damage observed is due mainly to singlet oxygen (1O2) and to a minor extent to hydroxyl radicals (.OH). The 1O2 generation and triplet lifetime of this porphyrin have also been estimated. Fluorescence spectroscopy, used to ascertain the binding of this porphyrin to the mitochondrial proteins, shows a rapid association within 0-2 h and a decline thereafter. Confocal microscopy reveals intracellular localisation of this porphyrin in cells in vitro. Our overall results suggest that the porphyrin H2T4CPP, due to its ability to bind to mitochondrial protein components and to generate ROS upon photoexcitation, may have potential applications in photodynamic therapy.

Animals↗

PubMed1999

Induction of permeability transition in pancreatic mitochondria by cerulein in rats.

Hyperstimulation with cholecystokinin analogue cerulein induces a mild edematous pancreatitis in rats. There is evidence for a diminished energy metabolism of acinar cells in this experimental model. The aim of this study was to demonstrate permeability transition of the mitochondrial inner membrane as an early change in mitochondrial function and morphology. As functional parameters, the respiration and membrane potential of mitochondria isolated from control and cerulein-treated animals were measured, and changes in volume and morphology were investigated by swelling experiments and electron microscopy. Five hours after the first injection of cerulein, the leak respiration was nearly doubled and the resting membrane potential was decreased by about 17 mV. These alterations were reversed by extramitochondrial ADP or did not occur when cyclosporin A was added to the mitochondrial incubation. A considerable portion of the mitochondria isolated from cerulein-treated animals was swollen and showed dramatic changes in morphology such as a wrinkled outer membrane and the loss of a distinct cristae structure. These data provide evidence for the opening of the mitochondrial permeability transition pore at an early stage of cerulein induced pancreatitis. This suggests that the permeability transition is an initiating event for lysis of individual mitochondria and the initiation of apoptosis and/or necrosis, as had been shown to occur in this experimental model.

Animals↗

PubMed1999

Prevention of age-related aneuploidies by polar body testing of oocytes.

PURPOSE: We previously demonstrated that aneuploidy-free oocytes may be preselected by testing the first and second polar bodies removed from oocytes following their maturation and fertilization. The present paper describes the results of the application of the method in 659 in vitro fertilization cycles from patients of advanced maternal age. METHODS: Using micromanipulation techniques, 3943 oocytes were tested by polar body sampling and fluorescent on situ hybridization analysis using specific probes for chromosomes 13, 18, and 21. RESULTS: Fluorescent in situ hybridization results were available for 3217 (81.6%) of 3943 oocytes studied, of which 1388 (43.1%) had aneuploidies; 35.7% of the aneuploidies were of first meiotic division origin, and 26.1% of second meiotic division origin. Most errors in the first meiotic division were represented by chromatid malsegregation. The transfer of embryos deriving from 1558 of 1829 aneuploidy-free oocytes in 614 treatment cycles resulted in 131 clinical pregnancies and 88 healthy children born after confirmation of the polar body diagnosis. CONCLUSIONS: Polar body testing of oocytes provides an accurate and reliable approach for prevention of age-related aneuploidies in in vitro fertilization patients of advanced maternal age.

Adult↗

PubMed1999

Birth of healthy children after preimplantation diagnosis of thalassemias.

BACKGROUND: Preimplantation genetic diagnosis (PGD) allows couples at risk of having children with thalassemia to ensure the healthy outcome of their pregnancy. METHODS: Seventeen PGD clinical cycles were initiated for Cypriot couples at risk of having children with different thalassemia mutations, including IVSI-110, IVSI-6, and IVS II-745. Unaffected embryos for transfer were selected by testing oocytes, using first and second polar body (PB) removal and nested polymerase chain reaction analysis followed by restriction digestion. RESULTS: Unaffected embryos were selected in 16 of 17 PGD cycles. Of 166 oocytes studied from these cycles, 110 were analyzed by sequential analysis of both the first and the second PB, resulting in preselection and transfer of 45 unaffected embryos. This resulted in seven pregnancies and in the birth of five healthy thalassemia-free children. The embryos predicted to have inherited the affected allele were not transferred. Analysis of these embryos confirmed the PB diagnosis. CONCLUSIONS: Sequential first and second PB testing of oocytes is reliable for PGD of thalassemia and is a feasible alternative to prenatal diagnosis in high-risk populations.

Alleles↗

PubMed1999

Interaction of nitric oxide donors and ascorbic acid on D-[3H] aspartate efflux from rat striatal slices.

There are conflicting reports in the literature concerning the neuroprotective effect of ascorbic acid on excitotoxic processes in which excessive glutamate release and nitric oxide are supposed to be major factors. To study the influence of ascorbate on the nitric oxide modulated glutamate release rat striatal slices, preloaded with the tritiated glutamate analog D-aspartate, were used. The high potassium-induced efflux of D-[3H]aspartate was concentration dependently stimulated by the nitric oxide donors sodium nitroprusside, S-nitroso-N-acetylpenicillamine (SNAP) or 5-amino 3-morpholinyl-1,2,3-oxadiazolium chloride (SIN-1), as well as by solutions of gaseous nitric oxide and, interestingly, by cyanide. Only the stimulation of D-[3H]aspartate release by SNAP and nitroprusside was affected by ascorbate in terms of a highly significant potentiation. Ascorbate was shown to exert its effect primarily by influencing the decomposition of these nitric oxide donors rather than by a direct interaction of ascorbate with nitric monoxide on glutamate release.

Animals↗

PubMed1999

Studies on the effect of dose size on the absorption of beta-carotene by the rat in vivo.

This study was carried out to choose between two hypotheses with respect to the regulation of beta-carotene (BC) conversion to retinol in the whole animal: uptake of BC into intestinal mucosa is limited by saturation of an intestinal receptor; or the conversion to retinol is limited by saturation of the conversion enzyme(s). Groups of rats were given five different dose levels of labeled BC by stomach tube. Labeled and total BC and retinol were isolated from tissues and intestinal contents after 4 h. Results showed a positive linear relationship between BC in the intestinal wall and the dose administered, with no saturation level up to 1440 micrograms administered. Per cent formation of newly formed retinol from newly absorbed (i.e., labeled) BC was 20-26% of the three lower dose groups, 10% for the highest dose. No retinyl esters could be detected in the intestine. Most of the administered BC was in the intestinal contents, about 100-times more than in the intestinal wall and mucosa. Newly formed retinol in plasma was about 10-times that in liver. Small amounts of newly absorbed BC were found in liver, but no labeled retinyl esters. These results suggest that the absorption of BC is very inefficient; that it does not occur through an intestinal receptor; that the formation of retinol is regulated at the level of the conversion enzyme(s).

Animals↗

PubMed1999

Identification of women with early breast cancer by analysis of p43-positive lymphocytes.

Regular screening mammographies and increasing knowledge of high-risk groups have resulted in an improvement in the rate of detection of smaller malignant lesions. However, uncertain minimal mammographic features frequently require further costly and often uncomfortable investigation, including repeat radiological controls or surgical procedures, before cancerous lesions can be identified. Placental isoferritin (p43), a protein with immunosuppressive effects, has been detected on the surface of lymphocytes taken from peripheral blood in patients with breast cancer. In this study we evaluated the sensitivity and specificity of the expression of p43-positive lymphocytes as a marker in early stage breast cancer and also investigated its expression on T-cell subpopulations. The presence of p43-positive lymphocytes was investigated using the monoclonal antibody CM-H-9 and flow cytometry in 76 women with controversial, non-palpable mammographic findings who were undergoing surgical biopsy. Patients with early breast cancer (n = 48) had significantly higher p43-positive cell values (median 3.83%, range 0.98-19.4) than patients with benign lumps (n = 28, median 1.43%, range 0.17-3.7) or controls (n = 22, median 1.3%, range 0.4-1.87) (P < 0.0001). At a cut-off level of 2% p43-positive cells a sensitivity of 91.7% and a specificity of 89.3% for detection of breast cancer could be reached. While the median ratio of total CD4+/CD8+ cells was 2.6, a ratio of 1.3 was found for the p43-positive subpopulation (P < 0.001), thus indicating a significant link between p43 and CD8+ cells. The determination of p43-positive lymphocytes in peripheral blood could serve as an additional diagnostic tool in patients with controversial mammographic findings and could also reduce the need for cost-intensive and often uncomfortable management of these patients.

Antigens, Neoplasm↗

PubMed1999

Cyclooxygenase metabolites mediate glomerular monocyte chemoattractant protein-1 formation and monocyte recruitment in experimental glomerulonephritis.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) has been shown to play a significant role in the recruitment of monocytes/macrophages in experimental glomerulonephritis. Whereas a number of inflammatory mediators have been characterized that are involved in the expression of MCP-1 in renal disease, little is known about repressors of chemokine formation in vivo. We hypothesized that cyclooxygenase (COX) products influence the formation of MCP-1 and affect inflammatory cell recruitment in glomerulonephritis. METHODS: The effect of COX inhibitors was evaluated in the antithymocyte antibody model and an anti-glomerular basement membrane model of glomerulonephritis. Rats were treated with the COX-1/COX-2 inhibitor indomethacin and the selective COX-2 inhibitors meloxicam and SC 58125. Animals were studied at 1 hour, 24 hours, and 5 days after induction of the disease. RESULTS: Indomethacin, to a lesser degree the selective COX-2 inhibitors, enhanced glomerular MCP-1 and RANTES mRNA levels. Indomethacin enhanced glomerular monocyte chemoattractant activity an the infiltration of monocytes/macrophages at 24 hours and 5 days. CONCLUSIONS: Our studies demonstrate that COX products may serve as endogenous repressors of MCP-1 formation in experimental glomerulonephritis. The data suggest that COX-1 and COX-2 products mediate these effects differently because the selective COX-2 inhibitors had less influence on chemokine expression.

Animals↗

PubMed1999

Monocyte chemoattractant protein-1 mediates collagen deposition in experimental glomerulonephritis by transforming growth factor-beta.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) plays a significant role in the recruitment of monocytes/macrophages in experimental glomerulonephritis (GN). Because recent evidence points to possible profibrogenic effects of leukocyte-derived factors in GN, this study was designed to evaluate the role of the chemokine MCP-1 in the fibrogenesis of experimental GN. METHODS: Rats with an anti-thy-1-induced GN were treated with a neutralizing antiserum against MCP-1. Glomerular collagen type IV, as a marker of glomerular matrix deposition, was assessed by Northern and Western blotting and immunohistology. Transforming growth factor-beta (TGF-beta), an important mediator of this matrix expansion, was studied by Northern and Western blotting. RESULTS: The induction of GN resulted in a significant increase of glomerular collagen type IV deposition and TGF-beta synthesis. The neutralization of MCP-1 significantly reduced the enhanced collagen type IV protein synthesis and deposition without affecting collagen mRNA expression. However, both the enhanced transcription and protein synthesis of TGF-beta were inhibited by anti-MCP-1 antiserum in nephritic animals. CONCLUSIONS: In this model of GN, MCP-1 has a fibrogenic effect through the stimulation of TGF-beta. MCP-1 is thus not only important for the recruitment of inflammatory cells, but also mediates glomerular matrix accumulation.

Animals↗

PubMed1999

Molecular mechanisms of diabetic renal hypertrophy.

Altered growth of renal cells is one of the early abnormalities detected after the onset of diabetes. Cell culture studies whereby renal cells are exposed to high glucose concentrations have provided a considerable amount of insight into mechanisms of growth. In the glomerular compartment, there is a very early and self-limited proliferation of mesangial cells with subsequent hypertrophy, whereas proximal tubular cells primarily undergo hypertrophy. There is overwhelming evidence from in vivo and cell culture studies that induction of the transforming growth factor-beta (TGF-beta) system mediates the actions of high ambient glucose and that this system is pivotal for the hypertrophy of mesangial and tubular cells. Other factors such as hemodynamic forces, protein glycation products, and several mediators (for example, angiotensin II, endothelin-1, thromboxane, and platelet-derived growth factor) may further amplify the synthesis of TGF-beta and/or the expression of its receptors in the diabetic state. Cellular hypertrophy can be characterized by cell cycle arrest in the G1 phase. The molecular mechanism arresting mesangial cells in the G1 phase of the cell cycle is the induction of cyclin-dependent kinase (CdK) inhibitors such as p27Kip1 and p21, which bind to and inactivate cyclin-CdK complexes responsible for G1-phase exit. High-glucose-induced activation of protein kinase C and stimulated TGF-beta expression appear to be essential for stimulated expression of p27Kip1. In addition, a decreased turnover of protein caused by the inhibition of proteases contributes to hypertrophy. The development of irreversible renal changes in diabetes mellitus such as glomerulosclerosis and tubulointerstitial fibrosis is always preceded by the early hypertrophic processes in the glomerular and the tubular compartments. It may still be debated whether diabetic renal hypertrophy will inevitably lead to irreversible fibrotic changes in the absence of other factors such as altered intraglomerular hemodynamics and genetic predisposition. Nevertheless, understanding cellular growth on a molecular level may help design a novel therapeutic approach to prevent or treat diabetic nephropathy effectively.

Animals↗

PubMed1999

Leptin stimulates proliferation and TGF-beta expression in renal glomerular endothelial cells: potential role in glomerulosclerosis [seecomments].

BACKGROUND: Leptin inhibits food intake and increases energy expenditure. Although the kidney expresses abundant transcripts of the short form of the leptin receptor (Ob-Ra), a role for this hormone in renal function remains unclear. Because individuals with massive obesity who may exhibit increased leptin serum concentrations develop renal glomerulosclerosis, we studied whether leptin can influence renal growth and profibrogenic processes. METHODS: The effects of recombinant leptin on proliferation and synthesis of transforming growth factor-beta1 (TGF-beta1) was investigated in cultured glomerular endothelial cells of the rat (GERs) and syngeneic mesangial cells. Furthermore, leptin receptor expression and potential signal transduction pathways were evaluated in GERs. In addition, leptin was also infused for different time periods (72 hr and 3 weeks) into naive rats. RESULTS: Recombinant mouse leptin induced proliferation of GERs, but not of syngeneic mesangial cells. Coincubation with angiotensin II and leptin exerts additive proliferative effects in GERs. An antileptin-receptor antibody totally abolished this proliferation but did not influence serum-induced proliferation. GER expressed high affinity receptors of the Ob-Ra type (Kd, 4 nM; Bmax, 9700 receptors/cell). Leptin also stimulated phosphorylation of STAT1alpha, and kinase inhibitors attenuated proliferation, suggesting a pivotal role of phosphorylation in this process. Incubation of GERs with leptin also induced mRNA expression of TGF-beta1 and enhanced secretion of this profibrogenic cytokine. Short-term leptin infusion (72 hr) into naive rats induced a significant proliferation, mainly restricted to glomerular endothelial cells, and enhanced glomerular TGF-beta1 mRNA levels. In rats continuously infused for three weeks with leptin, glomerular TGF-beta1 expression was still enhanced, and an additional increase in glomerular collagen type IV mRNA and protein expression was detected. These animals revealed an increase in proteinuria compared with control-infused rats. CONCLUSION: Our findings are the first in vitro and in vivo demonstration that leptin is a renal growth and profibrogenic factor. These results may be an important contribution to our understanding of how leptin can contribute to renal damage, characterized by endocapillary proliferation and subsequent development of glomerulosclerosis, in pathophysiological situations with high circulating levels such as in diabetics or obese individuals. Although the effects of leptin itself are moderate, growth-promoting and profibrogenic effects may be enhanced in concert with other factors such as angiotensin II.

Animals↗

PubMed1999

Molecular mechanisms of renal hypertrophy: role of p27Kip1.

There are two fundamentally different growth responses for cells comprising the nephron: hyperplasia or hypertrophy. Cells that progress through the normal cell cycle double their DNA content and eventually divide during mitosis. Those cells that hypertrophy stop the growth process in the G1-phase of the cell cycle; while they increase in size, protein and RNA content, they cannot duplicate their set of chromosomes because they never pass through the S-phase of the cell cycle. Hypertrophy may be an early compensatory mechanism to initially replace the loss of functioning tissue, however, this maladaptive process eventually fosters progressive loss of renal function. Since progression of the cell through the G1 to S-phases is regulated by cyclins D, E and A, which in turn bind and activate cyclin dependent kinases (CDKs), evidence has been accumulating on a particular CDK-inhibitor protein, p27Kip1, which is speculated to be a key to the complex process of the G1/S cell cycle transition. This article examines the mechanisms of the proliferative growth response following acute tubular necrosis, and compensatory hypertrophy of glomerular and tubule cells, with a particular focus on the protein p27Kip1.

Animals↗