piperidines and Glomerulonephritis

Obesity and being overweight are risk factors for kidney diseases. The spectrum ranges from glomerulomegaly with or without focal or segmental glomerulosclerosis, to diabetic nephropathy, to carcinoma of the kidney and nephrolithiasis. The first sign of renal injury is microalbuminuria or frank proteinuria, in particular in the presence of hypertension. The occurrence of microalbuminuria and/or chronic kidney insufficiency (glomerular filtration rate < 60 ml/min/1.73 m(2)) is related to the increasing number of components of the metabolic syndrome; that is, central obesity, elevated fasting blood glucose level, hypertriglycerides, low high-density lipoprotein cholesterol level and hypertension. Obesity-associated renal disease should be prevented or retarded by weight reduction following lifestyle modification (salt restriction, hypocaloric diet, aerobic exercise) or eventually by antiobesity medication or bariatric surgery. Rimonabant, a new antiobesity medication, showed beneficial potential effect in treating clusters of metabolic syndrome, which may ultimately suggest potential benefit in treating obesity-related glomerulopathy.

Topics: Disease Outbreaks; Glomerulonephritis; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; United Kingdom

Cyclin-dependent kinases (CDKs) have long been known to be the main facilitators of the cell proliferation cycle. However, they also play important roles in the regulation of the RNA polymerase II transcription cycle. Cancer cells display aberrant cell cycle regulation to gain proliferative advantages and they also appear to have an exaggerated dependence on RNA polymerase II transcriptional activity to sustain pro-survival and antiapoptotic signalling. A picture is now starting to emerge that both the cell-cycle and transcriptional functions of CDKs can be exploited pharmacologically with CDK inhibitors that possess appropriate selectivity profiles. In this article, recent advances into these mechanistic insights and how they can guide clinical development in terms of choice of indication are reviewed, as well as combinations with existing chemotherapies. An overview is also given of recent clinical trial results with the lead CDK inhibitor drug candidates seliciclib (CYC202, (R)-roscovitine; Cyclacel) and alvocidib (flavopiridol; Aventis-NCI), as well as the development of other clinical entries and advanced preclinical compounds. The discussion focuses on oncology, but we point out recent results with CDK inhibitors in virology and nephrology.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Clinical Trials as Topic; Cyclin-Dependent Kinases; Drug Resistance, Neoplasm; Female; Flavonoids; Glomerulonephritis; Hematologic Neoplasms; HIV Infections; Humans; Molecular Sequence Data; Piperidines; Protein Kinase Inhibitors; Purines; Roscovitine; Transcription, Genetic

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on

Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Disease Progression; Enalapril; Enzyme Inhibitors; Epoxide Hydrolases; Fibrosis; Glomerular Mesangium; Glomerulonephritis; Hypertension; Male; Mice; Phenylurea Compounds; Piperidines; Reperfusion Injury

Dipeptidyl peptidase (DPP)-4 is an enzyme that cleaves and inactivates incretin hormones capable of stimulating insulin secretion from pancreatic β-cells. DPP-4 inhibitors are now widely used for the treatment of type 2 diabetes. Experimental studies have suggested a renoprotective role of DPP-4 inhibitors in various models of diabetic kidney disease, which may be independent of lowering blood glucose levels. In the present study, we examined the effect of DPP-4 inhibitors in the rat Thy-1 glomerulonephritis model, a nondiabetic glomerular injury model. Rats were injected with OX-7 (1.2 mg/kg iv) and treated with the DPP-4 inhibitor alogliptin (20 mg·kg(-1)·day(-1)) or vehicle for 7 days orally by gavage. Alogliptin significantly reduced the number of CD68-positive inflammatory macrophages in the kidney, which was associated with a nonsignificant tendency to ameliorate glomerular injury and reduce proteinuria. Another DPP-4 inhibitor, anagliptin (300 mg·kg(-1)·day(-1) mixed with food) and a glucagon-like peptide-1 receptor agonist, exendin-4 (10 mg/kg sc), similarly reduced CD68-positive macrophage infiltration to the kidney. Furthermore, ex vivo transmigration assays using peritoneal macrophages revealed that exendin-4, but not alogliptin, dose dependently reduced monocyte chemotactic protein-1-stimulated macrophage infiltration. These data suggest that DPP-4 inhibitors reduced macrophage infiltration directly via glucagon-like peptide-1-dependent signaling in the rat Thy-1 nephritis model and indicate that the control of inflammation by DPP-4 inhibitors is useful for the treatment of nondiabetic kidney disease models.

Topics: Animals; Anti-Inflammatory Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antilymphocyte Serum; Cell Line; Chemokine CCL2; Chemotaxis; Cytoprotection; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Exenatide; Glomerulonephritis; Glucagon-Like Peptide-1 Receptor; Kidney Glomerulus; Macrophages, Peritoneal; Male; Mice, Inbred C57BL; Peptides; Piperidines; Proteinuria; Pyrimidines; Rats, Sprague-Dawley; Receptors, Glucagon; Signal Transduction; Uracil; Venoms

Autoantibody production and immune complex deposition within the kidney promote renal disease in patients with lupus nephritis. Thus, therapeutics that inhibit these pathways may be efficacious in the treatment of systemic lupus erythematosus. Bruton's tyrosine kinase (BTK) is a critical signaling component of both BCR and FcR signaling. We sought to assess the efficacy of inhibiting BTK in the development of lupus-like disease, and in this article describe (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-[2,4-difluorophenoxy]phenyl)-1H-pyrazole-4-carboxamide (PF-06250112), a novel highly selective and potent BTK inhibitor. We demonstrate in vitro that PF-06250112 inhibits both BCR-mediated signaling and proliferation, as well as FcR-mediated activation. To assess the therapeutic impact of BTK inhibition, we treated aged NZBxW_F1 mice with PF-06250112 and demonstrate that PF-06250112 significantly limits the spontaneous accumulation of splenic germinal center B cells and plasma cells. Correspondingly, anti-dsDNA and autoantibody levels were reduced in a dose-dependent manner. Moreover, administration of PF-06250112 prevented the development of proteinuria and improved glomerular pathology scores in all treatment groups. Strikingly, this therapeutic effect could occur with only a modest reduction observed in anti-dsDNA titers, implying a critical role for BTK signaling in disease pathogenesis beyond inhibition of autoantibody production. We subsequently demonstrate that PF-06250112 prevents proteinuria in an FcR-dependent, Ab-mediated model of glomerulonephritis. Importantly, these results highlight that BTK inhibition potently limits the development of glomerulonephritis by impacting both cell- and effector molecule-mediated pathways. These data provide support for evaluating the efficacy of BTK inhibition in systemic lupus erythematosus patients.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; B-Lymphocytes; Cell Proliferation; Disease Models, Animal; Female; Germinal Center; Glomerulonephritis; Kidney; Lupus Erythematosus, Systemic; Lymphocyte Activation; Mice; Mice, Inbred NZB; Piperidines; Plasma Cells; Protein-Tyrosine Kinases; Pyrazoles; Receptors, Fc; Signal Transduction; T-Lymphocytes

Slowly progressive renal injury is the major cause for ESRD. The model of progressive immune complex glomerulonephritis in autoimmune MRL(lpr/lpr) mice was used to evaluate whether chemokine receptor CCR1 blockade late in the disease course can affect progression to renal failure. Mice were treated with subcutaneous injections of either vehicle or BX471, a nonpeptide CCR1 antagonist, three times a day from week 20 to 24 of age [corrected]. BX471 improved blood urea nitrogen levels (BX471, 35.1 +/- 5.3; vehicle, 73.1 +/- 39.6 mg/dl; P < 0.05) and reduced the amount of ERHR-3 macrophages, CD3 lymphocytes, Ki-67 positive proliferating cells, and ssDNA positive apoptotic cells in the interstitium but not in glomeruli. Cell transfer studies with fluorescence-labeled T cells that were pretreated with either vehicle or BX471 showed that BX471 blocks macrophage and T cell recruitment to the renal interstitium of MRL(lpr/lpr) mice. This was associated with reduced renal expression of CC chemokines CCL2, CCL3, CCL4, and CCL5 and the chemokine receptors CCR1, CCR2, and CCR5. Furthermore, BX471 reduced the extent of interstitial fibrosis as evaluated by interstitial smooth muscle actin expression and collagen I deposits, as well as mRNA expression for collagen I and TGF-beta. BX471 did not affect serum DNA autoantibodies, proteinuria, or markers of glomerular injury in MRL(lpr/lpr) mice. This is the first evidence that, in advanced chronic renal injury, blockade of CCR1 can halt disease progression and improve renal function by selective inhibition of interstitial leukocyte recruitment and fibrosis.

Topics: Animals; Autoantibodies; Blood Urea Nitrogen; CD3 Complex; CD8-Positive T-Lymphocytes; Chemokines; Disease Progression; DNA; DNA, Single-Stranded; Fibrosis; Glomerulonephritis; In Situ Hybridization; Ki-67 Antigen; Kidney; Leukocytes; Lupus Nephritis; Lymphocytes; Macrophages; Mice; Mice, Inbred MRL lpr; Microscopy, Fluorescence; Phenylurea Compounds; Piperidines; Receptors, CCR1; Receptors, Chemokine; Renal Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; T-Lymphocytes; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Animals; Antigen-Antibody Complex; Barbiturates; BCG Vaccine; Benzimidazoles; Cyclophosphamide; Disease Models, Animal; Female; Fluorescent Antibody Technique; gamma-Globulins; Glomerulonephritis; Kidney Glomerulus; Mice; Nephrectomy; Nitrogen Mustard Compounds; Piperidines; Smallpox Vaccine; Vaccination