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V H Gattone

Publications and source records attributed to V H Gattone.

At least 37 records · Page 2Linked to original sources
PubMed1995

Effect of lovastatin on the development of polycystic kidney disease in the Han:SPRD rat.

Proliferation of tubular epithelial cells is a major element leading to cyst formation in Han:SPRD rats with autosomal dominant polycystic kidney disease (PKD). ras proteins are important in the control of renal cell proliferation, and ras gene expression is increased in PKD. Farnesyl pyrophosphate, an intermediate in the conversion of acetyl-CoA to cholesterol, is required for the activation of ras guanosine triphosphate (GTP)-binding proteins that are important in the execution of several cellular functions, including cell proliferation. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, such as lovastatin, reduce farnesyl production in responsive cells and thereby have potential for ameliorating the accelerated epithelial cell proliferation of PKD. We administered lovastatin to heterozygous (Cy/+) Han:SPRD rats (4 mg/kg/d subcutaneously) from age 4 to 10 weeks, a period of rapid cystic disease progression in these animals. Untreated male Cy/+ rats developed larger cystic kidneys and had more severe renal functional impairment than females, as reported previously. In males, lovastatin significantly decreased cystic kidney size (referenced to body weight), the volume density of cysts, and the serum urea nitrogen level 14.5%, 24.4%, and 25.6/%, respectively. The corresponding changes in females were insignificant, and lovastatin had no effect on kidney weight or serum urea nitrogen in homozygous (+/+) normal male animals. On the basis of these results we conclude that lovastatin diminishes the severity of PKD in heterozygous male Han:SPRD rats.

Analysis of Variance↗
PubMed1995

In vitro fluid secretion by epithelium from polycystic kidneys.

The size of the kidneys in patients with autosomal dominant polycystic kidney disease (ADPKD) is due in large measure to the accumulation of secreted fluid within thin-walled epithelial sacs. We measured the net transepithelial movement of liquid in response to forskolin in isolated, intact cysts excised from the surface of human ADPKD kidneys and in cultured, polarized monolayers of epithelial cells derived from ADPKD cysts. 10 excised cysts bathed symmetrically in control culture medium secreted fluid at a rate of 0.19 +/- 0.03 microliter/cm2 per hour after stimulation with forskolin (10 microM). Ouabain (100 microM) addition to the cavity fluid did not change the rate of fluid secretion of 10 forskolin-treated cysts, but addition of the glycoside to the external bathing medium fluid of nine cysts decreased secretion to -0.004 +/- 0.05 microliter/cm2 per hour. 24 monolayers absorbed fluid (range -0.029 to -0.412 microliter/cm2 per hour); by contrast, fluid was secreted (range 0.074 to 1.242 microliters/cm2 per hour) after stimulation with forskolin (10 microM). Ouabain (0.1 microM) in the basolateral but not in the apical medium inhibited fluid secretion. Forskolin increased the intracellular cyclic AMP content of ADPKD and MDCK monolayers by 236 and 196%, respectively. Six ADPKD monolayers had stable lumen negative transepithelial electrical potential differences (PDte) of -1.4 +/- 0.3 mV, positive short circuit currents (SCC) of 11.9 +/- 2.1 microAmp/cm2 and a tissue resistance (Rte) of 116 +/- 14 ohm.cm2. Forskolin increased SCC to 15.5 +/- 1.9 microAmp/cm2 (P < 0.005) and decreased Rte to 95 +/- 13 ohm.cm2 (P < 0.05); PDte remained stable at -1.4 +/- 0.3 mV. Ouabain (10 microM) had no effect when added to the apical medium, but in the basolateral medium decreased SCC to 1.7 +/- 0.3 microAmp/cm2 and PDte to -0.2 +/- 0.1 mV. We conclude that ADPKD cells in surface cysts have the potential to absorb or to secrete solutes and fluid. cAMP-mediated fluid secretion from the basolateral medium into the lumen of surface ADPKD cysts may be driven by anion transport.

Biological Transport↗
PubMed1994

The alpha 3 chain of type IV collagen induces autoimmune Goodpasture syndrome.

Human Goodpasture syndrome is a lethal form of autoimmune disease that is characterized by pulmonary hemorrhage and glomerulonephritis. The tissue injury is mediated by autoantibodies that bind to glomerular and alveolar basement membrane. The target autoantigen is alpha 3(IV) collagen, one of six genetically distinct chains that comprise type IV collagen, and the epitope is sublocalized to the noncollagenous domain (NC1) of the alpha 3 chain. The present study reports the unique capacity of alpha 3(IV)NC1 dimer from bovine kidney to aberrantly engage the immune system of rabbits to respond to self, mimicking the organ-specific form of the human disease, whereas the other chains of type IV collagen are nonpathogenic. However, alpha 3(IV)NC1 hexamer was nonpathogenic, suggesting the exposure of a pathogenic epitope upon dissociation of hexamer into dimers. Exposure of the pathogenic epitope by infection or organic solvents, events which are thought to precede Goodpasture syndrome, may be the principal factor in the etiology of the disease. The pathogenicity of alpha 3(IV) collagen brings full circle a decade of research that has identified four novel chains (alpha 3-alpha 6) of type IV collagen.

Animals↗
PubMed1994

Abnormalities of glycosphingolipid, sulfatide, and ceramide in the polycystic (cpk/cpk) mouse.

Polycystic kidney disease is a disorder marked by aberrant renal tubular epithelial cell proliferation and transport abnormalities. Sphingolipids are ubiquitous membrane components implicated in several cellular functions including cell membrane sorting, signaling, growth, ion transport, and adhesion. To investigate a potential pathogenic role for sphingolipids in cystic kidney disease, we studied the sphingolipid content and associated enzymatic activities of the kidneys from cpk/cpk mice and their phenotypically normal litter mates. The neutral glycolipids, including glucosylceramide and lactosylceramide, displayed a striking increase in 3-week-old cpk/cpk mice as did the acidic lipid, ganglioside GM3. However, a correspondingly significant decrease in sulfoglycolipid and ceramide concentration was observed in the cpk/cpk kidneys. Glucosylceramide synthase activity was higher in the kidneys of the cpk/cpk mice than in those of the controls. Kinetic analysis of the glucosylceramide synthase revealed the presence of an endogenous activator in the cystic kidney. A marked decrease in sulfotransferase activity was observed in both whole kidney homogenates and in microsomal preparations that was consistent with the decrement in sulfolipid content. The increase in GM3, glucosyl- and lactosylceramide may therefore be the result of impaired sulfolipid synthesis at the 3-week time point. While sulfolipid and glucosylceramide concentrations are not different at 1 and 2 weeks of age, ceramide concentrations in cystic kidneys are significantly reduced compared to kidneys from phenotypically normal mice. These results suggest that sphingolipids may play a potential role in the proliferative and transport abnormalities associated with cystic renal disease and the development of azotemia.

Animals↗
PubMed1994

Renal cysts in transgenic mice expressing transforming growth factor-alpha.

Transforming growth factor-alpha (TGF-alpha) is a member of the epidermal growth factor (EGF) family of proteins and, like EGF, elicits its cellular function by binding to the EGF receptor. EGF stimulation may have a role in several normal and pathologic processes in the kidney, and EGF has been implicated in the development of renal cysts in vitro and in human autosomal dominant polycystic kidney disease. We sought to determine whether renal expression of an EGF-like protein (TGF-alpha) could lead to the formation of renal cysts in vivo. We examined morphologic alterations to the normal kidney caused by renal expression of a TGF-alpha transgene linked to a mouse metallothionein promoter stably integrated into the genome of the CD1 mouse. TGF-alpha transgene expression was induced with exogenous zinc treatment starting at 4 weeks of age, and mice were killed at 8 weeks of age. The transgene was expressed at higher levels in female transgenic mice than in male transgenic mice. The augmented expression of the TGF-alpha transgene in females was associated with increased renal size and the development of renal epithelial cysts. Both male and female mice exhibited increases in glomerular size and mesangial volume density. These results provide evidence that stimulation by an endogenous EGF-like protein can lead to renal enlargement, glomerular mesangial expansion, and renal cyst formation.

Animals↗
PubMed1993

Immune system of the spontaneously hypertensive rat: II. Morphology and function.

The spontaneously hypertensive rat (SHR) is a stress-sensitive animal which exhibits moderate immune dysfunction that has been implicated in the onset of hypertension. In this study, we examined the morphology of SHR thymus and spleen and further characterized the immune deficiency using Wistar-Kyoto (WKY) and Fisher 344 (F-344) rats for comparison. The adult SHR thymus does not display the increase in medullary volume typically noted with aging and the volume density of the marginal zone is decreased in the spleen. In vivo tritiated-thymidine incorporation is also decreased in the spleen of unstimulated SHR. In mixed lymphocyte reactions (MLR), the proliferative response of SHR splenocytes is significantly decreased relative to controls, WKY and F-344. Addition of interleukin-1 (IL-1), interleukin-2 (IL-2), or indomethacin to the MLR cultures does not increase proliferation. The proliferative response to T cell receptor monoclonal antibody (mAb-TCR) or interleukin-2 (IL-2) are similarly impaired in the SHR. The depressed proliferative T cell response is reversed by prolactin. It is suggested that the SHR is a valuable model for the study of immune deficiency.

Animals↗
PubMed1993

Autosomal-dominant polycystic kidney disease in the rat.

Kaspareit-Rittinghausen described a rodent model of inherited polycystic kidney disease (PKD), the Han:SPRD rat [1, 2], in which heterozygotes develop renal cysts and renal failure (in males) over several months, whereas homozygous animals develop rapidly progressive renal enlargement that leads to death in a few weeks. In this study, we examined selected elements of the pathogenesis of this disease in heterozygotes and homozygotes from birth to advanced disease. Heterozygous male rats developed slowly progressive renal cystic disease with interstitial fibrosis and azotemia seen by six months of age. Female heterozygotes developed slowly progressive renal cystic disease, but did not develop interstitial fibrosis or azotemia. Epithelial cells lining cyst cavities showed various degrees of morphologic immaturity. Cyst walls also developed basement membrane thickening, especially in areas of cellular immaturity, suggesting an interrelationship between this basement membrane thickening and cellular dedifferentiation. Thickened basement membranes were associated with increased immunoreactivity for type IV collagen, laminin, and fibronectin. Homozygous rats developed massive renal enlargement, marked azotemia, and died near three weeks of age. Renal c-myc proto-oncogene expression was elevated in homozygous cystic infants and in adult heterozygotes. In situ hybridization showed high levels of c-myc mRNA in cyst epithelia, suggesting abnormal regulation of cellular proliferation in the cells lining cysts, as seen in other models of PKD. The Han:SPRD rat is the only well-documented animal model of inherited PKD with an autosomal-dominant inheritance pattern and appears to have several features which resemble human ADPKD.

Animals↗
PubMed1992

Immune system of the spontaneously hypertensive rat. I. Sympathetic innervation.

Extensive bidirectional interactions are believed to exist between the sympathetic nervous system and the immune system. The spontaneously hypertensive rat (SHR) is known to possess both increased sympathetic nervous system activity with increased tissue catecholamine levels in several peripheral organs and a moderate T lymphocyte immune deficiency. We examined the development of innervation in both primary (thymus) and secondary (spleen) organs of the immune system of the SHR compared to immunocompetent Wistar-Kyoto (WKY), Fisher 344 (F-344), and Long Evan (LE) rats from birth through 24 weeks. Using glyoxylic acid-induced histofluorescence to visualize monoaminergic nerve fibers, coded specimens were examined and morphologically evaluated for the extent and distribution of innervation. The innervation of the SHR thymus was significantly increased at 2 and 12 weeks of age over the other strains. Unlike the control strains, splenic innervation in SHR was delayed until 2 weeks of age when it suddenly became exuberant. At 12 weeks, the innervation of the SHR spleen was increased over all control strains. By 24 weeks the innervation had regressed to a level comparable to the levels of the other rat strains in these tissues. During the suckling period, the size (weight) of the WKY spleen was larger and the level of innervation was decreased compared to the other strains. These strain-related differences in the development of sympathetic innervation of thymus and spleen likely reflect the complex, bidirectional interplay between the nervous and the immune systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Renal cadmium deposition and injury as a result of accumulation of cadmium-metallothionein (CdMT) by the proximal convoluted tubules--A light microscopic autoradiography study with 109CdMT.

Chronic, but not acute, exposure to inorganic Cd produces renal damage. However, a single injection of cadmium bound to metallothionein (CdMT) produces renal injury. It is hypothesized that an interorgan redistribution of Cd as CdMT is responsible for the chronic nephrotoxic effect of Cd. To better understand the mechanism(s) of CdMT-induced nephrotoxicity, the intrarenal distribution of 109CdMT was examined. 109CdMT isolated from rat liver was injected into mice at a nonnephrotoxic dose (0.1 mg Cd/kg, iv). The radioactivity in the kidney reached a maximum level (85% of the dose) as early as 30 min following administration and remained essentially constant for up to 7 days after injection. Within the kidney, 109Cd distributed almost entirely to the cortex. Light microscopic autoradiography of the kidney showed that, within the cortex, 109Cd distributed preferentially to the S1 and S2 segments of the proximal convoluted tubules. Within the S1 and S2 segments, the concentration of 109Cd in the basal and apical parts of the cells was similar to that after the nonnephrotoxic dose of CdMT, but after a nephrotoxic dose (0.3 mg Cd/kg) the radioactivity distributed preferentially to the apical portion of the cells. In contrast, light microscopic autoradiography studies with 109CdCl2 revealed that 109Cd was more evenly distributed throughout the proximal tubules. Moreover, after administration of a large dose of inorganic Cd (3 mg Cd/kg), a similar concentration of Cd was found in the convoluted and straight proximal tubules. These data support the hypothesis that CdMT-induced nephrotoxicity might be due, at least in part, to its preferential uptake of CdMT into the S1 and S2 segments of the proximal tubules, the site of Cd-induced nephrotoxicity.

Animals↗
PubMed1992

Accumulation and degradation of the protein moiety of cadmium-metallothionein (CdMT) in the mouse kidney.

Of major concern in Cd toxicity is its ability to produce renal damage after chronic exposure in humans and experimental animals. Renal injury affects predominantly the proximal tubules and more specifically the first segments of these tubules. Similar toxic effects to the kidneys are observed after administration of cadmium bound to metallothionein (CdMT). Therefore, CdMT was used in this study as a model to understand the mechanism(s) of Cd nephrotoxicity. It has been recently demonstrated that Cd from CdMT was preferentially taken up by the proximal convoluted tubules. Therefore, the purpose of these studies was to determine if the organic portion of the complex was also accumulated in these tubules. [35S]CdMT prepared from rat liver was administered intravenously to mice at a nonnephrotoxic dose (0.1 mg Cd/kg). The radioactivity in the kidney showed maximum level (80% of the dose) 15 min after the injection. This preferential renal uptake was also observed after administration of various doses of [35S]CdMT. In contrast to the earlier observed persistency of 109Cd in the kidney after 109CdMT administration, 35S disappeared rapidly (with a half-life of approximately 2 hr), and 24 hr after injection of [35S]CdMT, there was very little 35S left in the kidneys. These observations indicate that the protein portion of CdMT is rapidly degraded after renal uptake of CdMT and the released Cd is retained in the kidney. Within the kidney, 35S distributed mainly to the cortex. Light microscopic autoradiography showed that [35S]CdMT preferentially distributed to the proximal convoluted tubule (S1 and S2), which is the site of nephrotoxicity. Within the S1 and S2 segments, a greater distribution of 35S to the apical portion of the cells was observed after administration of both a nonnephrotoxic (0.1 mg Cd/kg) and a nephrotoxic (0.3 mg Cd/kg) dose. 109Cd administered as 109CdMT also distributed to the apical portion of the S1 and S2 cells. Therefore, both the organic (35S) and inorganic (109Cd) portions of CdMT are rapidly and efficiently taken up by the S1 and S2 cells of the proximal tubules, the site of nephrotoxicity. These observations support the concept that CdMT is readily taken up by the proximal tubular cells as a complex, and then its protein portion is rapidly degraded to release Cd that binds permanently to intracellular sites and produces nephrotoxicity.

Animals↗
PubMed1992

Localization of overexpressed c-myc mRNA in polycystic kidneys of the cpk mouse.

The C57BL/6J-cpk mouse has a form of autosomal-recessive polycystic kidney disease characterized by the rapid growth of large collecting duct cysts and the development of severe renal failure usually by three to four weeks of age. Previous studies had shown higher steady-state levels of proto-oncogene mRNA in these cystic kidneys. It is now shown using nuclear run-on transcription that the c-fos and c-myc proto-oncogenes are transcribed at higher rates in cystic kidneys, and thus that increased transcription, in part, may account for the increased mRNA levels. c-myc mRNA was detected by in situ hybridization in nephron anlagen and elongating tubules of normal and cystic kidneys during late fetal and early neonatal kidney development. Localization of c-myc expression in the normal kidney decreased with age over the three-week postnatal period. By contrast, c-myc mRNA was found in cysts as early as three days of age, with increased levels at two and three weeks. c-myc expression was also elevated in apparently normal, non-dividing proximal tubules in three-week-old cystic animals. On the basis of these findings, we suggest that c-myc expression is linked to the proliferation of cells engaged in the primary cystogenic process, and that expression of this gene in proximal tubule cells of severely azotemic animals reflects the compensatory response of residual tubular epithelial cells to progressive renal dysfunction.

Animals↗
PubMed1992

Epidermal growth factor in the neonatal mouse salivary gland and kidney.

In the adult mouse, epidermal growth factor (EGF) is synthesized in granular convoluted tubule (intralobular) duct cells of the submandibular gland and in distal tubule cells of the kidney. The presence of EGF in developing tissues and maternal milk and the localization of EGF receptors in developing tissues suggest a role for EGF in developmental processes. The primary aims of the present study were to: (1) localize EGF and EGF-binding sites in the kidney and submandibular gland during neonatal development and (2) to determine the effect of exogenously administered EGF on cell proliferation in these two developing organs. In the present study, EGF was localized by immunocytochemistry in granular convoluted tubule cells of the submandibular gland initially on day 21 after birth and in distal tubule cells of the kidney on postnatal day 6. EGF binding in the kidney decreased after birth with some localization to the glomerulus. In submandibular glands of newborn and 10-day-old mice, EGF-binding sites were associated with both acinar and duct cells with peak binding at 10 days postnatally. Submandibular glands from 20-day-old mice demonstrated primarily ductal EGF-binding sites. Exogenously administered EGF induced a mitogenic response in acinar and interlobular duct cells of submandibular glands during the first week after birth. EGF treatment during this period had an inhibitory effect on 3H-thymidine incorporation into cellular compartments in the developing kidney. The identification of EGF-binding sites in the kidney and submandibular gland before the presence of EGF suggests that an EGF-like molecule such as transforming growth factor alpha (TGF-alpha) may be present as a potential ligand in these organs. In order to assess this possibility, developing kidneys and submandibular glands were stained with anti-TGF-alpha. These immunocytochemical studies localized TGF-alpha to the proximal tubule of the kidney and immature acinar cells of the newborn mouse. Our data strongly support an autocrine, juxtacrine or paracrine role for EGF and/or TGF-alpha in the regulation of cell proliferation and cytodifferentiation in the kidney and submandibular gland.

Animals↗
PubMed1992

Ultrastructural features of the rabbit proximal tubules.

The unique ultrastructure of the epithelial cells that line the entire length of the proximal tubule have been described. In particular, scanning electron microscopy has been used to illustrate the varied nature of the apical, lateral and basal surfaces of cells located along P1, P2 and P3. The functional implication of the highly specialized microanatomy of the basal cell surface remains an interesting area of investigation.

Animals↗
PubMed1991

The SGP-2 gene is developmentally regulated in the mouse kidney and abnormally expressed in collecting duct cysts in polycystic kidney disease.

Sulfated glycoprotein-2 (SGP-2) is a secreted, dimeric, glycosylated protein synthesized by a number of different epithelial cell types. Although its function is not yet understood, SGP-2 has been hypothesized to be involved in such diverse processes as the promotion of cell-cell interactions, spermatogenesis, modulation of the complement system, and programmed cell death. We have now found that the SGP-2 gene is developmentally regulated in the mouse kidney. SGP-2 gene expression is first detected in the condensing nephrogenic mesenchyme and is subsequently down-regulated during the maturation of the glomerular epithelia, proximal tubules, and collecting ducts. SGP-2 continues to be expressed in the mature kidney in distal tubules and in the urothelial lining of the calyx and papilla. We have also examined the expression of the SGP-2 gene in polycystic kidneys of the C57BL/6J-cpk mouse, a model of autosomal recessive polycystic kidney disease in which there is development of epithelial-lined cysts arising primarily from the collecting duct system. Abnormally high levels of SGP-2 mRNA were found in the cyst wall epithelium of polycystic kidneys. The expression of the SGP-2 gene in normal development suggests that it plays a role in differentiating epithelial structures; and the abnormally high levels of SGP-2 gene expression in polycystic kidneys suggests that the cells lining cysts are not fully differentiated. It is possible, therefore, that polycystic kidney disease is caused by a defective developmental process in which there is a delay in terminal differentiation.

Animals↗
PubMed1991

Murine infantile polycystic kidney disease: a role for reduced renal epidermal growth factor.

Polycystic kidney disease (PKD) represents a form of renal epithelial hyperplasia. The C57BL/6J-cpk mouse, which has an infantile form of PKD, has a dramatically reduced expression of renal prepro-epidermal growth factor (EGF) mRNA and immunoreactive protein. Since EGF promoted maturation of epithelia in the neonate, the relative lack of renal EGF may contribute to the development of the collecting duct cysts by delaying epithelial maturation.

Aging↗
PubMed1991

Postnatal maturation of rabbit renal collecting duct. II. Morphological observations.

The renal collecting duct exhibits cellular heterogeneity. An ultrastructural analysis of this nephron segment during maturation has been performed to determine morphological characteristics of developing principal and intercalated cells (IC). Apical surface features and cytoplasmic ultrastructure were best revealed by scanning electron microscopy and by transmission electron microscopy, respectively. Morphological maturity was assessed by comparing measurements of apical perimeter, vesicular profiles, and mitochondrial volume percent. In mature cortical collecting duct (CCD), approximately 30% of total cells were rich in mitochondria and generally dark in matrix staining, i.e., IC. Most IC in outer cortex were microvillated, whereas in inner cortex most IC were microplicated with interspersed microvilli. Only approximately 16% of cells in outer medullary collecting duct (OMCD, outer stripe) were IC, with light cytoplasm and large protruding apical surfaces covered exclusively with microplicae. Neonatal CCDs showed no IC in outer cortex; a single type of principal-like cell was found in outer cortical region. Neonatal IC in both CCDs and OMCDs showed smaller apical perimeters, vesicular volumes, and mitochondrial volume percents than did mature IC. Whereas the number of cortical IC was reduced in the newborn, IC were present in mature numbers in OMCD and appeared relatively more mature than did IC of CCD. Some (approximately 10%) of IC in neonatal CCD did not show an identifiable apical surface pattern. Principal cells from both newborn CCD and OMCD were also morphometrically immature. It is clear that the neonatal collecting duct undergoes postnatal proliferation and differentiation.

Animals↗
PubMed1991

A hereditary model of slowly progressive polycystic kidney disease in the mouse.

There are two known forms of hereditary polycystic kidney disease (PKD) in humans. Although both forms initiate early in life, autosomal recessive PKD is rapidly progressive to kidney failure shortly after birth whereas autosomal dominant PKD is slowly progressive, taking many years to end stage. Research in this field has been limited by the availability of suitable animal models of PKD. Recently the C57BL/6J-cpk mouse has been used to study the pathogenesis of rapidly progressive hereditary PKD. The study presented here describes a slowly progressive PKD in the DBA/2-pcy mouse. The disease trait is transmitted in an autosomal recessive pattern and was localized to chromosome 9 through linkage to the dilute coat color and transferrin genes. Whereas some cystic changes were seen in fetal and newborn affected mice, renal enlargement did not develop until after 8 weeks of age and azotemia did not develop until after 18 weeks of age. Renal cysts were identified in all segments of the nephron and collecting duct and progressively enlarged with age. Individual cysts were found to be lined by a single layer of epithelial cells in most areas, with focal polyps and mounds of cells principally in collecting duct cysts. Early stages of cyst formation were associated with some abnormalities of tubular and glomerular basement membranes and accelerated eruption of incisors. Late stages of the disease were characterized by azotemia and chronic renal interstitial inflammatory infiltrates in all affected animals and cerebral vascular aneurysms in a few. We conclude that the DBA/2-pcy mouse has a form of renal cystic disease that appears similar in many respects to that seen in the dominant form of human PKD.

Animals↗