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Biomedical subjects

H Rennke

Publications and source records attributed to H Rennke.

14 recordsLinked to original sources
PubMed2006

Renal vascular sclerosis is associated with inherited thrombophilias.

Vascular sclerosis is often seen in renal biopsies. It is usually associated with diabetes mellitus, hypertension, smoking, etc. However, whether inherited thrombophilic states such as factor V gene mutation, prothrombin gene mutation, and methylenetetrahydrofolate reductase (MTHFR) gene mutation are associated with the vascular sclerosis is not known. Renal biopsies that showed vascular disease were grouped into five groups: (1) diabetic patients, (2) hypertensive patients, (3) diabetic and hypertensive patients, (4) smokers, and (5) vascular sclerosis of unknown etiology (idiopathic renal disease). Renal biopsies with no vascular sclerosis were used as controls. Frozen tissue was analyzed for factor V Leiden mutation, prothrombin G20210A mutation, and MTHFR C677T. Factor V Leiden mutation and prothrombin G20210A mutation was not seen in patients with diabetes, hypertension, or smoking, whereas MTHFR C677T polymorphism in these groups was not significant, compared to the controls. In the idiopathic renal disease group, three of the 17 patients (17.6%) had prothrombin G20210A mutation, two of the 17 patients (11.8%) had the factor V Leiden mutation, and five of the 17 (29.4%) were homozygous for the MTHFR C677T polymorphism. When the data were evaluated as a whole, 10 mutations were found in 17 patients (P<0.0005 compared to controls) or eight of the 17 patients (47%) were observed to have at least one of the three forms of inherited thrombophilia (P<0.001 compared to controls). These findings indicate that renal vascular lesions, in the absence of diabetes, hypertension, or smoking appears to be associated with inherited thrombophilias.

Adult↗
PubMed2001

Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells.

The immunosuppressive effect of rapamycin is mediated by inhibition of interleukin-2-stimulated T cell proliferation. We report for the first time that rapamycin also inhibits growth factor-induced proliferation of cultured mouse proximal tubular (MPT; IC(50) ~1 ng/ml) cells and promotes apoptosis of these cells by impairing the survival effects of the same growth factors. On the basis of these in vitro data, we tested the hypothesis that rapamycin would impair recovery of renal function after ischemic acute renal failure induced in vivo by renal artery occlusion (RAO). Rats given daily injections of rapamycin or vehicle were subjected to RAO or sham surgery. Rapamycin had no effect on the glomerular filtration rate (GFR) of sham-operated animals. In rats subjected to RAO, GFR fell to comparable levels 1 day later in vehicle- and rapamycin-treated rats (0.25 +/- 0.08 and 0.12 +/- 0.05 ml. min(-1). 300 g(-1), respectively) (P = not significant). In vehicle-treated rats subjected to RAO, GFR increased to 0.61 +/- 0.08 ml. min(-1). 300 g(-1) on day 3 (P < 0.02 vs. day 1) and then rose further to 0.99 +/- 0.09 ml. min(-1). 300 g(-1) on day 4 (P < 0.02 vs. day 3). By contrast, GFR did not improve in rapamycin-treated rats subjected to RAO over the same time period. Rapamycin also increased apoptosis of tubular cells while markedly reducing their proliferative response after RAO. Furthermore, rapamycin inhibited activation of 70-kDa S6 protein kinase (p70(S6k)) in cultured MPT cells as well as in the renal tissue of rats subjected to RAO. We conclude that rapamycin severely impairs the recovery of renal function after ischemia-reperfusion injury. This effect appears to be due to the combined effects of increased tubular cell loss (via apoptosis) and profound inhibition of the regenerative response of tubular cells. These effects are likely mediated by inhibition of p70(S6k).

Acute Kidney Injury↗
PubMed2000

Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.

Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.

Actinin↗
PubMed1999

Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides.

INTRODUCTION: To investigate the role and mechanisms of indirect allorecognition in allograft rejection, we studied whether priming T cells with donor-derived MHC allopeptides could accelerate rejection in a vascularized allograft model. METHODS: Lewis recipients of fully mismatched Wistar Furth cardiac allografts were immunized before transplantation with donor MHC allopeptides. RESULTS: Animals immunized with immunogenic class II MHC allopeptides rejected their grafts in a significantly accelerated fashion compared with controls. Additional studies demonstrated that a single immunodominant RT1.D (HLA-DR like) allopeptide was responsible for accelerating the rejection process. Histological analysis of rejected allografts revealed marked vascular rejection in the accelerated, although not the control, group as well as severe cellular rejection. Peak production of IgM and IgG donor-specific alloantibodies was detected by flow cytometry 1 week earlier in the sera of the accelerated group compared with the control group. Immunohistological analysis of grafts from the accelerated compared with the control group showed increased endothelial deposition of IgG2b, C3, and fibrin, and up-regulation of class II MHC molecule expression. Increased intragraft expression of interferon-y and the interferon-gamma-induced chemokines, inducible protein-10 and Mig, and infiltration by activated mononuclear cells expressing CXCR3, the receptor for inducible protein-10 and Mig, was also seen. CONCLUSION: These novel data provide evidence of a definitive link between indirect allorecognition of donor-derived MHC class II peptides and the cellular and humoral mechanisms of vascularized allograft rejection.

Animals↗
PubMed1999

Long-term maintenance of therapeutic cyclosporine levels leads to optimal graft survival without evidence of chronic nephrotoxicity.

Since the introduction of cyclosporine into clinical use, a major area of concern within the transplant community has been the fear of chronic nephrotoxicity. Although progressive renal damage does appear to occur in native kidneys of heart and liver transplant patients receiving cyclosporine, it has been our contention that its use is not a major cause of deterioration in renal allografts. We therefore undertook a study of 91 consecutive renal transplants performed over a three-year period with a minimum graft survival of 1 year and a follow-up of 7-9 years. Serial serum creatinine values, iothalamate clearances and cyclosporine levels were obtained at 3 months after transplantation and yearly thereafter. Biopsies were performed on all grafts that had failed as well as on the majority of patients with deteriorating renal function, and were interpreted by two nephropathologists. As measured by iothalamate clearances, 65% of the patients in this series exhibited absolutely stable renal function despite the maintenance of cyclosporine levels of more than 200 ng/ml for 7-9 years. Since these stable patients did not reveal any decline in renal function, it therefore follows that they did not experience chronic cyclosporine nephrotoxicity. Furthermore, none of the patients with declining renal function or with failed grafts showed any evidence of nephrotoxicity on biopsy. Chronic cyclosporine nephrotoxicity may be a cause of declining function or graft loss with renal transplant recipients, but if so, it is exceedingly rare.

Creatine↗
PubMed1996

Fanconi's syndrome and tubulointerstitial nephritis in association with L-lysine ingestion.

We report a case of a 44-year-old woman who developed Fanconi's syndrome in association with the oral ingestion of L-lysine. L-lysine is widely available in health food stores and has been recommended in the lay press for the treatment and prevention of recurrent herpes simplex. The development of a severe tubulointerstitial nephritis, and eventual progression to chronic renal failure, underscores the importance of this entity, heretofore unrecognized in humans.

Adult↗
PubMed1996

Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis.

A mutation was targeted to the murine alpha3 integrin gene. Homozygous mutant mice survived to birth, but died during the neonatal period. The mutation caused abnormal kidney and lung development. Mutant kidneys displayed decreased branching of the medullary collecting ducts, although the number of nephrons was not altered. Proximal tubules exhibited two distinct subsets of abnormalities, with the epithelial cells either containing excess lysosomes or becoming microcystic. In addition, glomerular development was markedly affected. In mutant kidneys, the extent of branching of glomerular capillary loops was decreased, with capillary lumina being wider than normal. The glomerular basement membrane was disorganized and glomerular podocytes were unable to form mature foot processes. Branching of the bronchi in lungs of mutant mice was also decreased and the large bronchi extended to the periphery. These results indicate a role for integrin receptors in basement membrane organization and branching morphogenesis.

Animals↗
PubMed1993

Fibrin(ogen) is internalized and degraded by activated human monocytoid cells via Mac-1 (CD11b/CD18): a nonplasmin fibrinolytic pathway.

Fibrin(ogen) (FGN) is important for hemostasis and wound healing and is cleared from sites of injury primarily by the plasminogen activator system. However, there is emerging evidence in plasminogen activator-deficient transgenic mice that nonplasmin pathways may be important in fibrin(ogen)olysis, as well. Given the proximity of FGN and monocytes within the occlusive thrombus at sites of vascular injury, we considered the possibility that monocytes may play an ancillary role in the degradation and clearance of fibrin. We found that monocytes possess an alternative fibrinolytic pathway that uses the integrin Mac-1, which directly binds and internalizes FGN, resulting in its lysosomal degradation. At 4 degrees C, FGN binds to U937 monocytoid cells in a specific and saturable manner with a kd of 1.8 mumol/L. Binding requires adenosine diphosphate stimulation and is calcium-dependent. At 37 degrees C, FGN and fibrin monomer (FM) are internalized and degraded at rates of 0.37 +/- 0.13 and 0.55 +/- 0.03 microgram/10(6) cells/h by U937 cells, 1.38 +/- 0.02 and 1.20 +/- 0.30 microgram/10(6) cells/h by THP-1 cells, and 2.10 +/- 0.20 and 2.52 +/- 0.18 micrograms/10(6) cells/h by human peripheral blood mononuclear cells, respectively. The serine protease inhibitors, PPACK and aprotinin, and the specific elastase inhibitor, AAPVCK, do not significantly inhibit degradation. However, degradation is inhibited by chloroquine, suggesting that a lysosomal pathway is involved. Factor X, a competitive ligand with FGN for the Mac-1 receptor, also blocks degradation, as does a monoclonal antibody to the alpha-subunit of Mac-1. Autoradiography of radioiodinated, internalized FGN shows that FGN proteolysis by the pathway produces a unique degradation pattern distinct from that observed with plasmin. In a fibrin clot lysis assay, Mac-1-mediated fibrinolysis contributed significantly to total fibrinolysis. In summary, FGN is internalized and degraded by activated human monocytoid cells via Mac-1 in the absence of plasmin, thereby providing an alternative fibrinolytic pathway. Thus, in addition to the function of cell adhesion, integrins may also act as receptors that mediate the internalization and degradation of bound ligands.

Antibodies, Monoclonal↗
PubMed1984

Recovery of proximal tubular function from ischemic injury.

Fluid (sodium) reabsorption, total glucose efflux, and reabsorption of angiotensin II and insulin from the proximal convoluted tubule were studied in rats by in vivo microperfusion. After 35 min of total renal artery occlusion, function was assessed at two intervals, 0-1 h (early recovery, ER) and 2-4 h (late recovery, LR). Light and electron microscopic evaluation showed 60-75% loss of proximal convoluted tubule brush border membrane in ER and nearly complete restoration of brush border in LR. No other structural abnormalities were evident. Renal blood flow was unchanged from control during both ER and LR. During ER, fluid reabsorption was reduced to 29.8 +/- 5.2%, and total glucose efflux, at normal tubule loads, to 73.9 +/- 5.5% of control. However, angiotensin II and insulin reabsorption were unchanged. In LR, fluid reabsorption remained significantly reduced at 54.3 +/- 8.1% of control. Total glucose efflux from the proximal tubule was normal in LR at glucose loads of up to 400 pmol X min-1, but was significantly reduced at higher loads. Passive glucose efflux, measured in the presence of 10(-4)M phloridzin, was not altered by ischemia. Brief ischemia results in significant alterations in proximal tubular reabsorption of sodium and glucose, which correlate with a substantial loss of brush border during ER. However, despite restoration of cell morphology to normal in LR, transport defects for both sodium and glucose persist.

Absorption↗
PubMed1982

Subcellular distribution of iodothyronine 5'-deiodinase in cerebral cortex from hypothyroid rats.

We have examined iodothyronine deiodination in subcellular fractions of cerebral cortex obtained from hypothyroid rats. Enzymatic activities were measured at 37 degrees C in the presence of 20 mM dithiothreitol with 125I-labeled T4 and 125I-labeled rT3 as substrates for 5'-deiodination and 131I-labeled T3 as the substrate for the 5-deiodinase. Reaction products were separated by descending paper and/or ion-exchange chromatography. Cerebral cortex subcellular fractions were also characterized by marker enzyme analysis and electron microscopy. Under optimal reaction conditions more than 80% of the 5'-deiodinase was recovered after fractionation. Both 5'-deiodinase and (Na+ + K+)-ATPase showed similar subcellular distributions and were enriched approx. 3-fold in the easily sedimenting membrane fraction and nerve terminal plasma membranes. Crude microsomal membranes (6 X 10(6) g X min pellet) also showed 2-fold enrichment of these enzymes. Nuclei and isolated mitochondria were devoid of deiodinating activity. T4 and T3 5-deiodinating activity was absent in the easily sedimenting membranes and present but not enriched in particulate fractions containing microsomal membranes. These data suggest that iodothyronine 5'-deiodinase is associated with plasma membrane fractions in the cerebral cortex.

Animals↗