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John J Bissler

Publications and source records attributed to John J Bissler.

16 recordsLinked to original sources
PubMed2006

Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest.

Expression of spermidine/spermine N(1)-acetyltransferase (SSAT) increases in kidneys subjected to ischemia-reperfusion injury (IRI). Increased expression of SSAT in vitro leads to alterations in cellular polyamine content, depletion of cofactors and precursors of polyamine synthesis, and reduced cell proliferation. In our model system, a >28-fold increase in SSAT levels in HEK-293 cells leads to depletion of polyamines and elevation in the enzymatic activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase, suggestive of a compensatory reaction to increased polyamine catabolism. Increased expression of SSAT also led to DNA damage and G(2) arrest. The increased DNA damage was primarily due to the depletion of polyamines. Other factors such as increased production of H(2)O(2) due to polyamine oxidase activity may play a secondary role in the induction of DNA lesions. In response to DNA damage the ATM/ATR --> Chk1/2 DNA repair and cell cycle checkpoint pathways were activated, mediating the G(2) arrest in SSAT-expressing cells. In addition, the activation of ERK1 and ERK2, which play integral roles in the G(2)/M transition, is impaired in cells expressing SSAT. These results indicate that the disruption of polyamine homeostasis due to enhanced SSAT activity leads to DNA damage and reduced cell proliferation via activation of DNA repair and cell cycle checkpoint and disruption of Raf --> MEK --> ERK pathways. We propose that in kidneys subjected to IRI, one mechanism through which increased expression of SSAT may cause cellular injury and organ damage is through induction of DNA damage and the disruption of cell cycle.

Acetyltransferases↗
PubMed2006

Stathmin-deficient mice develop fibrosis and show delayed recovery from ischemic-reperfusion injury.

In kidneys subjected to ischemic reperfusion injury (IRI) stathmin, a tubulin-binding protein involved in the regulation of mitosis, is expressed in dedifferentiated and proliferating renal tubule cells during the recovery phase. To ascertain the role of stathmin in the recovery from ischemic kidney injury, stathmin-deficient (OP18-/-) and wild-type (WT) animals were subjected to experimental IRI. At 3, 7, and 14 days after reperfusion serum samples and kidneys were collected for the examination of parameters of renal function, morphology, and recovery. Our studies indicate that on day 14 after reperfusion OP18-/- mice have significant renal failure, whereas the creatinine levels of WT animals have returned to baseline. Compared with WT animals OP18-/- mice had more extensive tubular fibrosis. The examination of proliferating cell nuclear antigen expression indicated that OP18-/- animals have increased proliferative or DNA repair activity for a more prolonged duration. The OP18-/- animals also had an increased number of tubules with apoptotic cells. These results suggest that in stathmin-deficient mice subjected to IRI, the aberrant regulation of cell cycle progression, not observed under normal conditions, impairs or at least delays the process of tubular repair and recovery after acute renal injury.

Animals↗
PubMed2006

Embolization of renal angiomyolipomata in patients with tuberous sclerosis complex.

BACKGROUND: Renal angiomyolipomata can reduce renal reserve and lead to renal insufficiency and failure. Angiomyolipomata often have abnormal vasculature, with aneurysms that can hemorrhage. Treatment of angiomyolipomata greater than 4 cm in diameter is suggested to decrease the risk for hemorrhage. Nephron-sparing procedures are critical in patients because of their limited renal reserve. Embolization has been used to treat these tumors, but there are limited studies examining efficacy. Our study examines the efficacy of selective embolization in decreasing tumor burden, preventing hemorrhage, and preserving renal function. METHODS: We conducted a retrospective study of 16 patients with 20 angiomyolipomata on 18 kidneys who underwent 18 transcatheter transarterial embolization procedures. Aneurysm number and size were documented and tumor volumes were measured before and after embolization. Preprocedure and follow-up renal function also were measured. Changes in angiomyolipoma volume and kidney function were assessed for significance by using paired t-test. RESULTS: Before embolization, 7 angiomyolipomata had more than 5 aneurysms, 9 had 1 to 5 aneurysms, and 4 had no aneurysms, but showed tortuous dysmorphic arteries. Mean aneurysm size was 5 mm. In patients available for follow-up, 15 of 16 tumors had decreased in volume (mean decrease, 56.1%; P = 0.001). At an average of 40 months' follow-up, there have been no subsequent hemorrhages. Patients' decline in renal function was not significantly different from that expected because of the natural course of the disease. CONCLUSION: Selective embolization decreases tumor size, prevents hemorrhage, and preserves kidney function in patients with tuberous sclerosis with renal angiomyolipomata.

Adolescent↗
PubMed2005

A mechanistic approach to inherited polycystic kidney disease.

There are approximately six and a half million people, of the estimated world population of six billion, with inherited polycystic kidney disease. Polycystic kidney diseases have a broad spectrum of associated findings that distinguish and define them as specific disease states. The dysregulation of renal tubular epithelial cell biology, including cell polarity, cell signaling, proliferation and apoptosis, basement membrane and matrix abnormalities, and fluid transport, has been postulated to contribute to cystogenesis. Evidence is currently accumulating that supports an association of the primary cilium and basal body, as well as the focal adhesion assembly, with polycystic kidney diseases. Renal cystogenesis may be the result of a disruption of a critical feedback loop that regulates tissue morphology based on the epithelial cell environment.

Child↗
PubMed2005

DNA lesion-specific co-localization of the Mre11/Rad50/Nbs1 (MRN) complex and replication protein A (RPA) to repair foci.

The DNA damage response, triggered by DNA replication stress or DNA damage, involves the activation of DNA repair and cell cycle regulatory proteins including the MRN (Mre11, Rad50, and Nbs1) complex and replication protein A (RPA). The induction of replication stress by hydroxyurea (HU) or DNA damage by camptothecin (CAMPT), etoposide (ETOP), or mitomycin C (MMC) led to the formation of nuclear foci containing phosphorylated Nbs1. HU and CAMPT treatment also led to the formation of RPA foci that co-localized with phospho-Nbs1 foci. After ETOP treatment, phospho-Nbs1 and RPA foci were detected but not within the same cell. MMC treatment resulted in phospho-Nbs1 foci formation in the absence of RPA foci. Consistent with the presence or absence of RPA foci, RPA hyperphosphorylation was present following HU, CAMPT, and ETOP treatment but absent following MMC treatment. The lack of co-localization of phospho-Nbs1 and RPA foci may be due to relatively shorter stretches of single-stranded DNA generated following ETOP and MMC treatment. These data suggest that, even though the MRN complex and RPA can interact, their interaction may be limited to responses to specific types of lesions, particularly those that have longer stretches of single-stranded DNA. In addition, the consistent formation of phospho-Nbs1 foci in all of the treatment groups suggests that the MRN complex may play a more universal role in the recognition and response to DNA lesions of all types, whereas the role of RPA may be limited to certain subsets of lesions.

Acid Anhydride Hydrolases↗
PubMed2004

PKD1 intron 21: triplex DNA formation and effect on replication.

Although autosomal dominant polycystic kidney disease is transmitted in an autosomal dominant fashion, there is evidence that the pathophysiology of cystogenesis involves a second hit somatic mutation superimposed upon the inherited germline mutation within the renal tubule cells. The polypurine.polypyrimidine (Pu.Py) tract of PKD1 intron 21 may play a role in promoting somatic mutations. To better characterize this tract and to evaluate its potential to participate in mutagenesis, we investigated the thermodynamics of intramolecular triplex formation by 15 Pu.Py mirror repeat tracts from PKD1 intron 21 by 2D gel electrophoresis. We demonstrate that intramolecular triplexes form with modest superhelical tensions for all the tracts examined. Primer extension studies demonstrated significant polymerase arrest within the Pu.Py tracts in one direction of replication only. We found correlation between polymerization arrest and both the potential length of the triplex and superhelical tension of intramolecular triplex formation. The presence of a Pu.Py tract also led to a replication blockade and double-strand breakage using an SV40 in vitro replication assay with HeLa cell extracts. During DNA replication, the G-rich template of the PKD1 Pu.Py tracts may form a triplex structure with the nascent strand, thereby blocking replication and potentially leading to recombination and mutation.

DNA↗
PubMed2004

Renal angiomyolipomata.

Renal angiomyolipomata can exist as an imaging curiosity or represent a life-threatening condition. There are likely over 10 million people world-wide who have a renal angiomyolipomata and approximately one tenth of these people also have tuberous sclerosis complex. The optimum treatment of angiomyolipomata is focused on sparing renal tissue and has included no intervention, both total and partial nephrectomy, and embolization. As basic science investigation into the biology of angiomyolipomata progresses, there is even hope for successful drug therapy. Because these renal lesions can be associated with other organ system dysfunction, a number of medical specialists become involved in the care of affected patients. The purpose of this article is to update the nephrologist on the molecular understanding of renal angiomyolipomata and for the possibilities of pharmacologic therapy in the future.

Angiomyolipoma↗
PubMed2003

Unpaired structures in SCA10 (ATTCT)n.(AGAAT)n repeats.

A number of human hereditary diseases have been associated with the instability of DNA repeats in the genome. Recently, spinocerebellar ataxia type 10 has been associated with expansion of the pentanucleotide repeat (ATTCT)(n).(AGAAT)(n) from a normal range of ten to 22 to as many as 4500 copies. The structural properties of this repeat cloned in circular plasmids were studied by a variety of methods. Two-dimensional gel electrophoresis and atomic force microscopy detected local DNA unpairing in supercoiled plasmids. Chemical probing analysis indicated that, at moderate superhelical densities, the (ATTCT)(n).(AGAAT)(n) repeat forms an unpaired region, which further extends into adjacent A+T-rich flanking sequences at higher superhelical densities. The superhelical energy required to initiate duplex unpairing is essentially length-independent from eight to 46 repeats. In plasmids containing five repeats, minimal unpairing of (ATTCT)(5).(AGAAT)(5) occurred while 2D gel analysis and chemical probing indicate greater unpairing in A+T-rich sequences in other regions of the plasmid. The observed experimental results are consistent with a statistical mechanical, computational analysis of these supercoiled plasmids. For plasmids containing 29 repeats, which is just above the normal human size range, flanked by an A+T-rich sequence, atomic force microscopy detected the formation of a locally condensed structure at high superhelical densities. However, even at high superhelical densities, DNA strands within the presumably compact A+T-rich region were accessible to small chemicals and oligonucleotide hybridization. Thus, DNA strands in this "collapsed structure" remain unpaired and accessible for interaction with other molecules. The unpaired DNA structure functioned as an aberrant replication origin, in that it supported complete plasmid replication in a HeLa cell extract. A model is proposed in which unscheduled or aberrant DNA replication is a critical step in the expansion mutation.

Base Composition↗
PubMed2003

Renal, hepatic, and marrow dysfunction in a patient with chronic renal insufficiency.

Severe illness with acute renal failure, leukopenia, thrombocytopenia, and coagulopathy frequently occurs with hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, hematological malignancies, sepsis, and collagen-vascular diseases. We present a 16-year-old male fast-food worker with underlying chronic renal insufficiency who manifested these abnormalities as a result of Ehrlichia chaffeensis sepsis. Doxycycline therapy and aggressive supportive care led to complete recovery.

Adolescent↗
PubMed2002

Infantile dilated X-linked cardiomyopathy, G4.5 mutations, altered lipids, and ultrastructural malformations of mitochondria in heart, liver, and skeletal muscle.

Mutations in the Xq28 gene G4.5 lead to dilated cardiomyopathy (DCM). Differential splicing of G4.5 results in a family of proteins called "tafazzins" with homology to acyltransferases. These enzymes assemble fatty acids into membrane lipids. We sequenced G4.5 in two kindreds with X-linked DCM and in two unrelated men, one with idiopathic DCM and the other with DCM of arrhythmogenic right ventricular dysplasia. We examined the ultrastructure of heart, liver, and muscle biopsy specimens in these three DCM types; we used gas chromatography to compare fatty acid composition in heart, liver, and muscle autopsy specimens of two patients of kindred 1 with that of controls. In X-linked DCM, G4.5 had a stop codon (E188X), a nonsense mutation, in kindred 1 and an amino acid substitution (G240R), a missense mutation, in kindred 2. In the two men with isolated DCM, G4.5 was not mutated. Ultrastructural mitochondrial malformations were present in the biopsy tissues of the patients with DCM. Cardiac biopsy specimens of both kindreds with X-linked DCM exhibited greatly enlarged mitochondria with large bundles of stacked, compacted, disarrayed cristae that differed from those of the two types of isolated DCM. Autopsy tissue of patients with X-linked DCM had decreased unsaturated and increased saturated fatty acid concentrations. Seven of 13 published G4.5 missense mutations, including the one presented here, occur in acyltransferase motifs. Impaired acyltransferase function could result in increased fatty acid saturation that would decrease membrane fluidity. Mitochondrial membrane proliferation may be an attempt to compensate for impaired function of acyltransferase. Cardiac ultrastructure separates X-linked DCM with G4.5 mutations from the two types of isolated DCM without G4.5 mutations. Electron microscopy of promptly fixed myocardial biopsy specimens has a role in defining the differential diagnosis of DCM. Mutational analysis of the G4.5 gene also serves this purpose.

Acyltransferases↗
PubMed2002

Reduction of postembolization syndrome after ablation of renal angiomyolipoma.

Approximately 75% of patients with tuberous sclerosis complex develop renal angiomyolipomas. These hamartomatous lesions distort and damage renal parenchyma and can lead to hemorrhage. To reduce the risk of hemorrhage, transarterial embolization is used to necrose the angiomyolipoma while sparing normal renal tissue. Although an effective renal-sparing procedure, embolization most often is associated with an inflammatory response that causes significant fever and pain that can last for several days despite the use of acetaminophen. Reported cases show that 49 of 55 patients who underwent embolization developed this syndrome. The use of such nonsteroidal anti-inflammatory drugs as aspirin is contraindicated because of their adverse effects on platelet function. To reduce pain and fever associated with postembolization syndrome (PES), we changed our clinical management of patients postembolization to include a tapering dose of prednisone over a 2-week period. Nine patients underwent this pharmacological intervention, and one patient abstained. All patients were monitored for pain and fever. Only two patients treated with steroids developed fever, which was assuaged with acetaminophen, and no patient reported pain. The tapering dose of prednisone was well tolerated, and there were no postprocedure infections. The use of a short-term tapering dose of prednisone appeared to reduce PES compared with the reported literature and improved patient comfort.

Acetaminophen↗
PubMed2002

Apolipoprotein J/clusterin prevents a progressive glomerulopathy of aging.

Apoliprotein J (apoJ)/clusterin has attracted considerable interest based on its inducibility in multiple injury processes and accumulation at sites of remodeling, regression, and degeneration. We therefore sought to investigate apoJ/clusterin's role in kidney aging, as this may reveal the accumulated effects of diminished protection. Aging mice deficient in apoJ/clusterin developed a progressive glomerulopathy characterized by the deposition of immune complexes in the mesangium. Up to 75% of glomeruli in apoJ/clusterin-deficient mice exhibited moderate to severe mesangial lesions by 21 months of age. Wild-type and hemizygous mice exhibited little or no glomerular pathology. In the apoJ/clusterin-deficient mice, immune complexes of immunoglobulin G (IgG), IgM, IgA, and in some cases C1q, C3, and C9 were detectable as early as 4 weeks of age. Electron microscopy revealed the accumulation of electron-dense material in the mesangial matrix and age-dependent formation of intramesangial tubulo-fibrillary structures. Even the most extensively damaged glomeruli showed no evidence of inflammation or necrosis. In young apoJ/clusterin-deficient animals, the development of immune complex lesions was accelerated by unilateral nephrectomy-induced hyperfiltration. Injected immune complexes localized to the mesangium of apoJ/clusterin-deficient but not wild-type mice. These results establish a protective role of apoJ/clusterin against chronic glomerular kidney disease and support the hypothesis that apoJ/clusterin modifies immune complex metabolism and disposal.

Aging↗
PubMed2002

Tuberous sclerosis complex: renal imaging findings.

PURPOSE: To review the renal imaging findings and changes over time in a large series of young patients with tuberous sclerosis complex (TSC). MATERIALS AND METHODS: One hundred thirty-nine renal imaging studies (113 ultrasonographic scans, 15 computed tomographic scans, and 11 magnetic resonance images) were identified in 59 patients with TSC (mean age, 11.4 years; age range, 3 days to 36 years). There were 31 male and 28 female patients. Angiomyolipomas and cysts were identified and characterized according to the following features: number, unilateral versus bilateral, largest diameter, and change over time. In patients whose initial examination results were normal, the age at onset of lesions was noted. The chi(2) test was used to determine whether cysts and angiomyolipomas occurred in different subpopulations. RESULTS: Angiomyolipomas were identified in 47 (80%) patients and were too numerous to count in 36 (76%), focal in 38 (81%), and bilateral in 42 (89%). The mean largest diameter was 21 mm. Cysts were identified in 28 (47%) patients, 18 (64%) of whom had fewer than five cysts. Cysts were bilateral in 17 (61%) patients. The mean largest diameter was 20 mm. In patients with initially normal examination results, the mean age at presentation was 9.0 years for those with cysts and 9.2 years for those with angiomyolipomas. In 80 follow-up examinations, size and/or number increased in 32 (40%) angiomyolipomas and 21 (26%) cysts. Cysts and angiomyolipomas did not occur in significantly different subpopulations (P =.13). CONCLUSION: Both angiomyolipomas and cysts occur commonly in pediatric patients with TSC and tend to increase in size and number with increasing age. Angiomyolipomas are more common than cysts and tend to be numerous.

Adolescent↗