piperidines and Ureteral-Obstruction

Although the effects of dipeptidyl peptidase 4 (DPP-4) inhibitors beyond their hypoglycemic action have been reported, whether these inhibitors have renoprotective effects in nondiabetic chronic kidney disease (CKD) is unclear. We examined the therapeutic effects of DPP-4 inhibition in mice with unilateral ureteral obstruction (UUO), a nondiabetic model of progressive renal fibrosis. After UUO surgery, mice were administered either the DPP-4 inhibitor alogliptin or a vehicle by oral gavage once a day for 10 days. Physiological parameters, degrees of renal fibrosis and inflammation, and molecules related to renal fibrosis and inflammation were then evaluated using sham-operated mice as controls. Positive area of α-smooth muscle actin was significantly smaller and expression of transforming growth factor β messenger RNA was significantly lower in the alogliptin-treated group than in the vehicle-treated group. Renal total collagen content was also significantly lower in the alogliptin-treated group than in the vehicle-treated group. These results suggest that alogliptin exerted renoprotective antifibrotic effects. The positive area of F4/80 was significantly smaller and expression of CD68 messenger RNA was significantly lower in the alogliptin-treated group than in the vehicle-treated group, suggesting an anti-inflammatory action by the DPP-4 inhibitor. Compared to the results for the vehicle-treated group, expression of markers for M1 macrophages tended to be lower in the alogliptin-treated group, and the relative expression of M2 macrophages tended to be higher. These data indicate the various protective effects of DPP-4 inhibition in nondiabetic mice with UUO. DPP-4 inhibitors may therefore be promising therapeutic choices even for nondiabetic CKD patients.

Topics: Actins; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Blood Urea Nitrogen; Calcium-Binding Proteins; Creatinine; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Fibrosis; Kidney; Macrophages; Male; Mice; Mice, Inbred C57BL; Piperidines; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Uracil; Ureteral Obstruction

Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. There is a need to explore new therapeutic pathways to reduce renal fibrogenesis. To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys. The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney. Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-β1 stimulation. The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis. Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.

Topics: Acute Disease; Animals; Arachidonic Acids; Cells, Cultured; Chemokine CCL2; Collagen; Diabetes Mellitus; Disease Models, Animal; Endocannabinoids; Fibrosis; Gene Expression Profiling; Glomerulonephritis, IGA; Glycerides; Humans; Kidney; Ligands; Macrophages; Mice; Mice, Knockout; Myofibroblasts; Nephritis, Interstitial; Oligonucleotide Array Sequence Analysis; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; RNA, Messenger; Transforming Growth Factor beta1; Up-Regulation; Ureteral Obstruction

Renal fibrosis is a final common manifestation of CKD resulting in progressive loss of kidney function. Bone marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. However, the signaling mechanisms underlying the activation of bone marrow-derived fibroblast precursors in the kidney are not fully understood. In this study, we investigated the role of the Janus kinase 3 (JAK3)/signal transducer and activator of transcription (STAT6) signaling pathway in the activation of bone marrow-derived fibroblasts. In cultured mouse monocytes, IL-4 or IL-13 activated STAT6 and induced expression of α-smooth muscle actin and extracellular matrix proteins (fibronectin and collagen I), which was abolished by a JAK3 inhibitor (CP690,550) in a dose-dependent manner or blocked in the absence of STAT6. In vivo, STAT6 was activated in interstitial cells of the obstructed kidney, an effect that was abolished by CP690,550. Mice treated with CP690,550 accumulated fewer bone marrow-derived fibroblasts in the obstructed kidneys compared with vehicle-treated mice. Treatment with CP690,550 also significantly reduced myofibroblast transformation, matrix protein expression, fibrosis development, and apoptosis in obstructed kidneys. Furthermore, STAT6-deficient mice accumulated fewer bone marrow-derived fibroblasts in the obstructed kidneys, produced less extracellular matrix protein, and developed much less fibrosis. Finally, wild-type mice engrafted with STAT6(-/-) bone marrow cells displayed fewer bone marrow-derived fibroblasts in the obstructed kidneys and showed less severe renal fibrosis compared with wild-type mice engrafted with STAT6(+/+) bone marrow cells. Our results demonstrate that JAK3/STAT6 has an important role in bone marrow-derived fibroblast activation, extracellular matrix production, and interstitial fibrosis development.

Topics: Actins; Animals; Apoptosis; Bone Marrow Transplantation; Cells, Cultured; Collagen Type I; Extracellular Matrix Proteins; Fibroblasts; Fibronectins; Fibrosis; Interleukin-13; Interleukin-4; Janus Kinase 3; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Myofibroblasts; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction; STAT6 Transcription Factor; Ureteral Obstruction

Topics: Analgesia, Epidural; Anesthesia, Intravenous; Antiemetics; Benzhydryl Compounds; Chemical and Drug Induced Liver Injury; Clomipramine; Contraindications; Humans; Hypnotics and Sedatives; Intracellular Signaling Peptides and Proteins; Intraoperative Complications; Kidney Pelvis; Modafinil; Narcolepsy; Neuropeptides; Ondansetron; Orexins; Pain, Postoperative; Piperidines; Preanesthetic Medication; Propofol; Remifentanil; Ureteral Obstruction

In a prospective study, from September 2000 to September 2001, all ureteroscopies ( n=140) were performed under local and intravenous patient controlled analgesia using continuous infusion of remifentanil (Ultiva). The dosage of 0.15 micro g/kg/min was adapted to changing intraoperative pain (range 0.08-0.30 micro g/kg/min). Preoperative sedation with midazolam 2 mg was given 5 min prior to ureteroscopy. The efficacy of monitored anesthesia care ("Big MAC") was quantified by the patient using a visual analogue pain scale. A total of 97.1% (136/140) of the procedures were performed and finished under remifentanil. Only four male patients underwent conversion to general anesthesia due to insufficient analgesia. All but one patient would choose remifentanil again for first line anesthesia. Significant differences in pain scale values were noticed for male/female patients and ureteroscopies above/below the iliac vessel crossing. Side effects were rare being mainly hypoxic events (pO(2)<90% in 5.1%). Indication, intraoperative procedure, average surgery time (24 min), complications and primary success rate (96.6/90/63.3% stone free for distal/mid/proximal ureter, respectively) did not differ from the control group under general anesthesia. Ureteroscopies with remifentanil are safe, universally applicable because of refifentanil's organ independent esterase metabolism and as effective as general anesthesia. There is no need for PACU stay for patients due to the ultra-short drug half-life, and therefore remifentanil is cost effective and perfect in an outpatient setting.

Topics: Carcinoma, Renal Cell; Conscious Sedation; Diagnosis, Differential; Dose-Response Relationship, Drug; Efficiency; Female; Humans; Infusions, Intravenous; Kidney Calculi; Kidney Neoplasms; Male; Midazolam; Pain Measurement; Patient Satisfaction; Piperidines; Remifentanil; Retrospective Studies; Ureteral Calculi; Ureteral Obstruction; Ureteroscopy

Small-intestinal submucosa (SIS) has been successful as an onlay graft in ureteral repair, but tubularized segment interposition of SIS has been unsuccessful. Our objective was to evaluate whether a type I collagen inhibitor, halofuginone, would prevent stricture formation in tubularized SIS interposition.. We performed either laparoscopic partial ureteral excision followed by an SIS onlay graft (N = 5) or complete laparoscopic ureteral excision followed by an SIS interposition graft (N = 7) in domestic pigs. Animals received either no (N = 3), low-dose (N = 5), or high-dose (N = 4) halofuginone. Animals had ureteral stenting for 2 weeks after surgery and were permitted to survive for 6 or 9 weeks. An intravenous urogram (IVU) was performed prior to sacrifice. Kidneys were examined grossly and histologically.. One animal that received an onlay graft died of an unrelated illness. The remaining four ureteral onlay animals, including one control and two low-dose and one high-dose pig, had grossly normal kidneys at harvest. The IVU was normal in the control and high-dose animal but showed delayed excretion with mild hydroureteronephrosis in the low-dose animals. Pathologic examination of the SIS site revealed circumferential reepithelialization with inflammation and mild fibrosis. All seven tubularized interposition graft kidneys demonstrated either severe hydroureteronephrosis (N = 5) or renal atrophy (N = 2), and all had complete obstruction on IVU. Pathologic examination revealed a stenotic ureteral lumen with extensive surrounding inflammation and fibrosis.. An SIS onlay graft was successful in the porcine model of ureteral injury. Halofuginone, a type I collagen inhibitor, did not demonstrate a significant beneficial effect in this technique. Ureteral tubularized interpositions with SIS are unsuccessful and not improved by halofuginone.

Topics: Animals; Collagen Type I; Female; Intestinal Mucosa; Intestine, Small; Piperidines; Postoperative Complications; Protein Synthesis Inhibitors; Quinazolines; Quinazolinones; Swine; Ureter; Ureteral Obstruction