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Biomedical subjects

Gunter Wolf

Publications and source records attributed to Gunter Wolf.

69 records · Page 4Linked to original sources
PubMed2002

Leptin and renal disease.

Leptin is a small peptide hormone that is mainly, but not exclusively, produced in adipose tissue. The circulating leptin concentration therefore directly reflects the amount of body fat. Leptin was identified through positional cloning of the obese (ob) gene, which is mutated in the massively obese ob/ob mouse, and it has a pivotal role in regulating food intake and energy expenditure. It binds to the so-called long receptor (Ob-Rb) in the hypothalamus and regulates food intake through the release of other neurotransmitters. Moreover, leptin exerts several other important metabolic effects on peripheral tissue, including modification of insulin action, induction of angiogenesis, and modulation of the immune system. As a small peptide, leptin is cleared principally by the kidney. Not surprisingly, serum leptin concentrations are increased in patients with chronic renal failure and those undergoing maintenance dialysis. Whether the hyperleptinemia of chronic renal failure contributes to some uremic manifestations, such as anorexia and weight loss, requires additional investigation. The kidney expresses abundant concentrations of the truncated isoform of the leptin receptor Ob-Ra, but only a small amount of the full-length receptor Ob-Rb. We recently discovered that leptin has direct effects on renal pathophysiological characteristics. Both cultured glomerular endothelial cells and mesangial cells obtained from the diabetic db/db mouse possess the Ob-Ra receptor, but whether biological effects of leptin are transduced through this receptor remains unknown. In glomerular endothelial cells, leptin stimulates cellular proliferation, transforming growth factor-beta1 (TGF-beta1) synthesis, and type IV collagen production. Conversely, in mesangial cells, leptin upregulates synthesis of the TGF-beta type II receptor, but not TGF-beta1, and stimulates glucose transport and type I collagen production through signal transduction pathways involving phosphatidylinositol-3-kinase. These data suggest that leptin triggers a paracrine interaction in which glomerular endothelial cells secrete TGF-beta, to which sensitized mesangial cells may respond. Both cell types increase their expression of extracellular matrix in response to leptin. Infusion of leptin into normal rats for 3 weeks fosters the development of focal glomerulosclerosis and proteinuria. Additional previously described direct and indirect effects of leptin on the kidney include natriuresis, increased sympathetic nervous activity, and stimulation of reactive oxygen species. These findings collectively suggest that the kidney is not only a site of leptin metabolism, but also a target organ for leptin action in pathophysiological states.

Animals↗
PubMed2002

No association between a genetic variant of the p22(phox) component of NAD(P)H oxidase and the incidence and progression of IgA nephropathy.

BACKGROUND: The course of glomerulonephritis varies even within the same histological entity, which suggest that genetic factors determine the progression of inflammatory renal diseases. We studied a potential relationship between the C242T gene polymorphism of p22(phox), a subunit of the NAD(P)H oxidase, and frequency as well as progression of immunoglobulin A (IgA) nephropathy. Patients with lupus nephritis were also investigated. The distribution of the C242T gene variation of p22(phox) has not been previously studied in patients with renal disease. METHODS: Patients with IgA nephropathy were from a homogenous ethnic group of patients living in Northern Germany (n=127). Patients with active lupus nephritis WHO classes III/IV (n=46) were also studied. All diagnoses were confirmed by renal biopsy. Healthy blood donors (n=151) exhibited a genotype distribution similar to previously reported values for Caucasians (CC, 41.2%; CT, 45%; TT, 13.8%). However, C242T genotype distribution was not significantly different (chi(2) test) in patients with IgA nephropathy (CC, 44.9%; CT, 48%; TT, 7.1%) or in active lupus nephritis (CC, 54.3%; CT, 34.7%; TT, 11%). Grouping of IgA nephropathy patients as those with mild renal impairment at the time of biopsy (serum creatinine <1.3 mg/dl) and those with more severe renal failure (serum creatinine >1.3 mg/dl) also failed to show a relationship with p22(phox) polymorphism. Log-rank analysis for up to 15 years in selected cases of IgA nephropathy did not show a significant difference in renal survival rate among the three genotypes. CONCLUSIONS: It appears that the C242T polymorphism is not associated with IgA nephropathy or active lupus nephritis and may not affect the progressive deterioration of renal function in patients with IgA nephropathy. However, whether the C242T polymorphism plays a role in other renal diseases remains to be studied.

Biopsy↗
PubMed2002

Angiotensin II and tubular development.

Accumulating evidence suggests that angiotensin II (ANG II) plays an important role in the complex affair of renal organogenesis. The renin-angiotensin system (RAS) is up-regulated during renal development and in the perinatal period. On the other hand, inhibition of the RAS, for example by angiotensin-converting enzyme (ACE) inhibitors, may produce specific renal abnormalities including abnormal renal vessels, failure to develop a renal pelvis and tubular atrophy associated with expansion of the interstitium. AT2 receptors are expressed abundantly during fetal development and are down-regulated markedly after birth, whereas the abundance of AT1 receptors increases as maturation proceeds. Mice with targeted deletions of genes for angiotensinogen or ACE revealed severe renal abnormalities. In contrast, AT1A, AT1B and AT2 receptor knockout animals exhibited milder abnormalities of the kidney. These findings suggest that AT1 and AT2 receptors are both involved in the development of the nephron, and that ANG II provides signals through both receptors. ANG II exerts in vitro growth-stimulatory effects on tubular cells. Moreover, ANG II induces synthesis of collagen type IV in tubular cells, a necessary prerequisite for successful basement membrane formation. These effects are mediated through AT1 receptors. Thus, it is feasible that blockade of the RAS during kidney organogenesis leads to a decrease in the growth factor ANG II that may be pivotal for tubular growth and differentiation. On the other hand, ANG II's growth-stimulatory effects through AT1 receptors may be counterbalanced by AT2 receptor-mediated apoptosis and growth inhibition. Therefore, alterations in AT2 receptor signalling may alter the delicate balance between growth stimulation and inhibition, leading to alterations in tubular formation.

Angiotensin II↗
PubMed2002

The hypertrophic effect of transforming growth factor-beta is reduced in the absence of cyclin-dependent kinase-inhibitors p21 and p27.

Transforming growth factor-beta (TGF-beta) has both antiproliferative and hypertrophic effects on mesangial cells (MC). However, it is not known if these processes are independent or if they share common signaling pathways. Proliferation and hypertrophy are regulated by specific cell-cycle regulatory proteins, where the cyclin-dependent kinase (CDK) inhibitors inhibit target cyclin-CDK complexes. This study examined whether the growth regulatory effects of TGF-beta were determined by the CDK inhibitors p21 and p27. Accordingly, cultured MC from wild type (+/+) and single and double null (-/-) p21 and p27 mice were grown in 5% serum in the presence or absence of TGF-beta1 (2 ng/ml). Proliferation ([(3)H]-thymidine incorporation, cell number, cell cycle) and hypertrophy ([(3)H]-leucine incorporation, total protein content, forward light scatter) were measured after 24 h, 48 h, and 96 h. TGF-beta inhibited proliferation in +/+ and p21/p27 double -/- MC to a similar extent. TGF-beta induced hypertrophy in +/+ MC (18.0% increase at 48 h), and to lesser extent in p21 -/- (12.8%) and p27 -/- MC (11.5%) measured by forward light scatter analysis. In p21/p27 double -/-, the hypertrophic effects of TGF-beta were significantly reduced (3.9% at 48 h). Similar results were obtained by measuring hypertrophy by total protein and [(3)H]-leucine incorporation. In conclusion, the CDK inhibitors p21 and p27 are not required for the antiproliferative effects of TGF-beta. However, the hypertrophic growth effects of TGF-beta are reduced in the absence of both p21 and p27. These data suggest that the regulation of the antiproliferative and hypertrophic effects of TGF-beta may be distinct processes.

Animals↗
PubMed2002

Angiotensin II's antiproliferative effects mediated through AT2-receptors depend on down-regulation of SM-20.

Angiotensin II (ANG II) inhibits proliferation and induces differentiation through AT2 receptors. However, target genes involved in this process are not well characterized. We studied PC12 cells, a rat pheochromocytoma cell line exclusively expressing AT2 receptors. ANG II attenuated proliferation of PC12 cells without concomitant induction of apoptosis. To identify potential novel genes involved in the antimitogenic actions of ANG II, we performed differential display analysis of PC12 cells after challenge with 10(-7) M ANG II for 6 hours. One identified gene selected for further study that was down-regulated by ANG II in PC12 cells was SM-20. This gene has been previously isolated from vascular smooth muscle cells treated with mitogens by differential hybridization. Recent findings show a homology of SM-20 with enzymes involved in the regulation of hypoxia inducible factor 1. ANG II suppressed mRNA expression of SM-20 in PC12 cells after only 30 minutes, as detected by Northern blotting. This effect was antagonized by an AT2 receptor blocker, but not by losartan. A rabbit polyclonal antibody was generated against a peptide sequence of SM-20 and detected a major band of the predicted size of 40 kd and a second 33-kd band that likely represents a processed form present in mitochondria. Immunohistochemistry revealed a granular staining of the cytoplasm of PC12 cells compatible with a previously described mitochondrial localization of SM-20 protein. Western blots confirmed the down-regulation of SM-20 protein in PC12 cells subsequent to incubation with ANG II. SM-20 transcripts were also reduced by ANG II acting on AT2 receptors in rat glomerular endothelial cells that express both AT1 and AT2 receptors. SM-20 antisense, but not sense, phosphothioate-modified oligonucleotides reduced base-line proliferation of PC12 cells. In contrast, inducible overexpression of SM-20 using the ecdysone system prevented the antiproliferative effects of ANG II in PC12 cells. In summary, our study identified SM-20 as an essential component of ANG II's growth-suppressive effects mediated through AT2 receptors. This gene apparently plays an important role in the regulatory processes determining whether a cell should undergo differentiation, apoptosis, or proliferation.

Angiotensin II↗
PubMed2002

Existence of a regulatory loop between MCP-1 and TGF-beta in glomerular immune injury.

Glomerular upregulation of monocyte chemotactic protein-1 (MCP-1), followed by an influx of monocytes resulting eventually in extracellular matrix deposition is a common sequel of many types of glomerulonephritis. However, it is not entirely clear how early expression of MCP-1 is linked to the later development of glomerulosclerosis. Because transforming growth factor-beta (TGF-beta) is a key regulator of extracellular matrix proteins, we hypothesized that there might be a regulatory loop between early glomerular MCP-1 induction and subsequent TGF-beta expression. To avoid interference with other cytokines that may be released from infiltrating monocytes, isolated rat kidneys were perfused with a polyclonal anti-thymocyte-1 antiserum (ATS) and rat serum (RS) as a complement source to induce glomerular injury. Renal TGF-beta protein and mRNA expressions were strongly stimulated after perfusion with ATS-RS. This effect was attenuated by coperfusion with a neutralizing anti-MCP-1 but was partly mimicked by perfusion with recombinant MCP-1 protein. On the other hand, renal MCP-1 expression and production were stimulated by administration of ATS-RS. Additional perfusion with an anti-TGF-beta antibody further aggravated this increase, whereas application of recombinant TGF-beta protein reduced MCP-1 formation. Our data demonstrate an intrinsic regulatory loop in which increased MCP-1 levels stimulate TGF-beta formation in resident glomerular cells in the absence of infiltrating immune competent cells.

Animals↗
PubMed2001

Cyclooxygenase-2 overexpression inhibits platelet-derived growth factor-induced mesangial cell proliferation through induction of the tumor suppressor gene p53 and the cyclin-dependent kinase inhibitors p21waf-1/cip-1 and p27kip-1.

Cyclooxygenase-2 (COX-2) is an inducible enzyme and serves as a source of paracrine prostaglandin E2 (PGE2) formation in many tissues. In glomerular immune injury COX-2 formation is up-regulated in association with increased mesangial cell growth. To examine whether COX-2 exerts growth modulating effects on glomerular cells, we established two separate COX-2-overexpressing mesangial cell lines (COX-2+) and assessed their proliferative response to the potent mesangial cell growth-promoting factor, platelet-derived growth factor (PDGF). PDGF increased proliferation in mock-transfected cells. In contrast, PDGF did not induce proliferation in COX-2+ cells. Our results also showed that the tumor suppressor protein p53 and the cyclin-dependent kinase inhibitors p21(cip-1) and p27(kip-1) were up-regulated in COX-2+ cells de novo as well as under PDGF-stimulated conditions. To study whether COX-2 products are required for these effects, COX-2+ cells were treated with indomethacin (1 microg/ml) or NS-398 (3 microm). Unexpectedly, both COX inhibitors had no significant effect on cell proliferation, not on the protein levels of p53, p21(cip-1), or p27(kip-1). To evaluate the role of p21(cip-1) and p27(kip-1), COX-2 was overexpressed in mesangial cells derived from p21(cip-1) (p21-/- COX-2+) and p27(kip-1) (p27-/- COX-2+) null mice. In contrast to the wild type COX-2+ cells, p21-/- COX-2+ and p27-/- COX-2+ cells proliferated in response to PDGF. These data suggest that COX-2 inhibits mesangial cell proliferation by a novel mechanism that is independent of prostaglandin synthesis, but involves p53, p21(cip-1), and p27(kip-1).

Animals↗
PubMed2000

Reactive oxygen species stimulate p44/42 mitogen-activated protein kinase and induce p27(Kip1): role in angiotensin II-mediated hypertrophy of proximal tubular cells.

Angiotensin II (AngII) induces G(1) phase arrest and hypertrophy of cultured renal proximal tubular cells. In previous studies, it was shown that these effects depend on oxygen radical-mediated induction of p27(Kip1), an inhibitor of cyclin-dependent kinases. The present study was undertaken to investigate whether mitogen-activated protein (MAP) kinases serve as signaling intermediates between AngII-induced oxidative stress and induction of p27(Kip1). AngII (10(-7) M) induces a biphasic phosphorylation pattern of p44/42 MAP kinase with an early phosphorylation after 2 min and a later, second phosphorylation peak after prolong incubation (12 h) in cultured proximal tubular cells from two different species (MCT and LLC-PK(1) cells). Total protein expression of MAP kinase was not changed by AngII. These phosphorylation patterns of p44/42 MAP kinase caused activation of the enzyme, as detected by phosphorylated MAP substrate Elk-1 after immuno-precipitation of MAP kinase. Exogenous H(2)O(2) also stimulates a biphasic phosphorylation of p44/42 MAP kinase. The flavoprotein inhibitor diphenylene iodinium, as well as the antioxidant N-acetylcysteine, prevented AngII-induced p44/42 MAP kinase phosphorylation, indicating involvement of reactive oxygen species generated by membrane-bound NAD(P)H oxidase. The MAP kinase kinase inhibitor PD98059 completely inhibits AngII-induced p27(Kip1) expression and (3)[H]leucine incorporation into proteins as a previously established marker of cell hypertrophy. PD98059 did not attenuate AngII-stimulated intracellular synthesis of oxygen radicals. Transient transfection with p44/42 MAP kinase antisense, but not sense, phosphorothioate-modified oligonucleotides also prevented AngII-induced MAP kinase phosphorylation, p27(Kip1) expression, and cell hypertrophy. Furthermore, induction of p27(Kip1) by H(2)O(2) was also abolished in the presence of PD98059. Although AngII induces phosphorylation of the stress-activated p38 MAP kinase, inhibition of this enzyme with SB203580 failed to attenuate induced p27(Kip1) expression and hypertrophy. These data provide evidence that AngII- mediated oxygen stress leads to the phosphorylation of p44/42 MAP kinase in proximal tubular cells. Activation of this enzyme is essential for p27(Kip1) expression, G(1) phase arrest, and hypertrophy of proximal tubular cells. These findings may lead to new concepts concerning interference of the development of proximal tubular hypertrophy, which may eventually turn into a maladaptive process in vivo leading ultimately to tubular atrophy and tubulointerstitial fibrosis.

Angiotensin II↗
PubMedDate not supplied

Normative data for digital X-ray radiogrammetry from a female and male German cohort.

This study presents German reference data for digital X-ray radiogrammetry (DXR) differentiated by males as well as females, and quantifies for gender-specific and age-related differences including all DXR parameters. This study also documents the effects of different X-ray settings (e.g., radiographs of the wrist or the hand) on DXR measurements. There were 2085 patients who were prospectively enrolled (954 females and 1131 males) from a data pool of 11,915 patients with radiographs of the nondominant hand or wrist. All patients underwent measurements of bone mineral density (BMD), cortical thickness, bone width, and the metacarpal index (MCI) using DXR technology. These data showed a continuous age-related increase of the DXR parameters to the point of peak bone mass, then a continuous decline beyond the peak bone mass with accentuated age-related cortical bone loss in women. Peak bone mass is reached at approximately 30-34 yr for women and 45-49 yr for men. In addition, men had a significantly higher DXR BMD (mean: +12.8%) compared with woman in all age groups. Regarding the impact of various X-ray settings (e.g., X-ray(wrist) vs. X-ray(hand)), no significant difference was observed between both groups, men as well as women. The development of digital imaging technology has enabled more precise measurements of several radio-geometric features. The present study estimated normative reference values for DXR in German Caucasian women and men. Based on this reference data, a valid and reliable quantification of disease-related demineralization based on measurements of DXR BMD and MCI is now available for the Caucasian ethnic group.

Absorptiometry, Photon↗
PubMedDate not supplied

Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis.

Angiotensin II (ANG II) induces cell-cycle arrest of cultured proximal tubular cells, resulting in cellular hypertrophy. This ANG II-mediated hypertrophy is associated with the induction of p27(Kip1), an inhibitor of G1 phase cyclin-dependent kinase cyclin complexes. We have recently demonstrated that ANG II-mediated expression of p27(Kip1) and induction of cellular hypertrophy depend on the generation of reactive oxygen species (ROS). The effects of ROS are mediated by stimulation of mitogen-activated protein (MAP) kinases. p44/42 MAP kinase directly phosphorylates p27(Kip1) at serine-threonine residues and increases thereby its half-life time. AT2-receptor activation has been implicated in apoptosis and/or cell differentiation. Recent studies, however, revealed a more indirect role of hypoxia in the antiproliferative effects of ANG II transduced through AT2 receptors. We found that SM-20 is down-regulated in ANG II-stimulated PC12 cells that express only AT2 receptors. It turned out that SM20 is the rat homologue of a dioxygenase that regulates hypoxia-inducible factor 1 (HIF-1). ANG II induces HIF-1alpha by a posttranscriptional mechanism suggesting that SM20 down-regulation leads to stabilization of HIF-1. Thus, ANG II-induced ROS generation plays a pivotal role in several pathophysiological situations, leading to renal growth regulation and remodeling after injury.

Angiotensin II↗
PubMedDate not supplied

Friedrich Theodor von Frerichs (1819-1885) and Bright's disease.

BACKGROUND: Richard Bright (1789-1858) discovered that edema and proteinuria are linked with renal disease. Friedrich Theodor von Frerichs (1819-1885) performed microscopic studies on Bright's disease and wrote the first German textbook of nephrology. The present contribution analyzes Frerichs' work. METHODS: Frerichs' career and his book Die Bright'sche Nierenkrankheit und deren Behandlung are examined in terms of contemporary medical knowledge. RESULTS: Frerichs conducted clinical and microscopic studies that led him to conclude that Bright's disease is a single pathological entity with many possible causes. Frerichs identified three stages through which the condition progresses. Although an oversimplification, Frerichs' various stages are reflected in the current notion that chronic renal disease, irrespectively of its etiology, relentlessly progresses to end-stage renal failure with common features of tubulointerstitial fibrosis and tubular atrophy. After writing his monograph, Frerichs never touched on renal disease again and is actually better known for his contributions to hepatology. Frerichs was a volatile and difficult person who was not always fair to his students and colleagues. CONCLUSION: Frerichs put the study of renal diseases on the map in Germany and made the novel observation that chronic renal diseases follow similar morphological patterns despite multiple origins.

Germany↗