fr-167653 and Kidney-Diseases

Natriuretic peptides exert multiple effects by binding to natriuretic peptide receptors (NPRs). Osteocrin (OSTN) binds with high affinity to NPR-C, a clearance receptor for natriuretic peptides, and inhibits degradation of natriuretic peptides and consequently enhances guanylyl cyclase-A (GC-A/NPR1) signaling. However, the roles of OSTN in the kidney have not been well clarified. Adriamycin (ADR) nephropathy in wild-type mice showed albuminuria, glomerular basement membrane changes, increased podocyte injuries, infiltration of macrophages, and p38 mitogen-activated protein kinase (MAPK) activation. All these phenotypes were improved in OSTN- transgenic (Tg) mice and NPR3 knockout (KO) mice, with no further improvement in OSTN-Tg/NPR3 KO double mutant mice, indicating that OSTN works through NPR3. On the contrary, OSTN KO mice increased urinary albumin levels, and pharmacological blockade of p38 MAPK in OSTN KO mice ameliorated ADR nephropathy. In vitro, combination treatment with ANP and OSTN, or FR167653, p38 MAPK inhibitor, reduced Ccl2 and Des mRNA expression in murine podocytes (MPC5). OSTN increased intracellular cyclic guanosine monophosphate (cGMP) in MPC5 through GC-A. We have elucidated that circulating OSTN improves ADR nephropathy by enhancing GC-A signaling and consequently suppressing p38 MAPK activation. These results suggest that OSTN could be a promising therapeutic agent for podocyte injury.

Topics: Animals; Disease Models, Animal; Doxorubicin; Kidney Diseases; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle Proteins; p38 Mitogen-Activated Protein Kinases; Podocytes; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Signal Transduction; Transcription Factors; Up-Regulation

Nephronophthisis (NPHP), the most frequent genetic cause of end-stage kidney disease in children and young adults, is characterized by a variable number of renal cysts associated with cortical tubular atrophy and interstitial fibrosis. The p38 mitogen-activated protein kinase (MAPK) pathway is an important intracellular signaling pathway involved in the production of profibrotic mediators. The relationship between p38 MAPK and renal fibrosis in NPHP2 is unknown.. We administered a selective p38 MAPK inhibitor, FR167653, in a NPHP2 mouse model (inv/inv, invΔC mice) from 3 to 6 weeks old, and the kidneys were examined at 6 weeks of age. Phosphorylation of p38 MAPK (p-p38 MAPK) protein levels, the degree of renal fibrosis, messenger RNA (mRNA) levels for extracellular matrix genes and mRNA levels for transforming growth factor in the kidneys were studied. Effect of an extracellular signal-regulated protein kinase (ERK) kinase (MEK) inhibitor on renal fibrosis was also evaluated.. Expression of extracellular matrix genes and p-p38 MAPK were increased in the NPHP2 mouse model kidney. FR167653 successfully decreased p-p38 MAPK levels, the degree of fibrosis and extracellular matrix gene expressions. However, the FR167653 did not prevent cyst expansion, abnormal cell proliferation and acceleration of apoptosis and did not influence ERK activation. In contrast, MEK inhibition reduced both cyst expansion and fibrosis without affecting p38 MAPK activation.. These results suggest that inhibition of p38 MAPK reduced renal fibrosis but not cyst expansion, cell proliferation and apoptosis in NPHP2 model mice. Our results suggest that p38 MAPK and ERK signaling pathways independently affect renal fibrosis in inv mutant mice.

Topics: Animals; Apoptosis; Blotting, Western; Cell Proliferation; Cysts; Disease Models, Animal; Fibrosis; Growth Inhibitors; Humans; Kidney Diseases; Mice; Mice, Transgenic; p38 Mitogen-Activated Protein Kinases; Pyrazoles; Pyridines; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcription Factors

The p38 mitogen-activated protein kinase (MAPK) pathway is an important intracellular signalling pathway involved in the production of proinflammatory and profibrotic mediators. Previous reports indicated the role of p38 MAPK activation in renal fibrosis.. We administered a selective p38 alpha MAPK inhibitor, FR167653, in a mouse model of unilateral ureteral obstruction (UUO) during the late stage (Days 7-14) after UUO, and the kidneys were examined at Day 14. p38 and phospho-p38 MAPK protein levels, the degree of renal fibrosis, the degree of myofibroblast accumulation and macrophage infiltration, and mRNA levels for TGF-beta1 and alpha1(I) collagen in the kidneys were assessed.. FR167653 treatment caused marked decreases in phospho-p38 MAPK levels along with decreased fibrosis at Day 14 after UUO. Although myofibroblast accumulation and alpha1(I) collagen mRNA level were decreased, no significant change was observed in the number of interstitial macrophages and TGF-beta1 mRNA level with FR167653 treatment.. These results suggest that p38 MAPK blockade is an appealing therapeutic target, even after the emergence of established fibrosis.

Topics: Animals; Base Sequence; Collagen Type I; Collagen Type I, alpha 1 Chain; DNA Primers; Fibroblasts; Fibrosis; Kidney Diseases; Macrophages; Male; Mice; Mice, Inbred C57BL; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; RNA, Messenger; Time Factors; Transforming Growth Factor beta1; Ureteral Obstruction

Ischemia-reperfusion injury is one of the central nonimmunologic processes involved in renal allograft dysfunction. Kidneys from non-heart beating donors (NHBD) exhibit higher rates of delayed graft function (DGF) than those from other donors. Primary nonfunction and DGF are the main barriers to the use of kidneys from NHBD. Using a pig model of NHBD transplantation, we studied the effect of FR167653 (a p38 MAP kinase inhibitor) on the recovery and reparation of kidneys exposed to both warm (WI: 1 h) and cold ischemia (24 h). Our results demonstrate that the addition of FR167653 increases the kinetics of proximal tubule cell regeneration after 60 min of WI. Hypoxia-inducible factor and vascular endothelial growth factor expression was also more important in FR167653-treated kidneys compared with those in nontreated groups. Also, expression of peripheral-type benzodiazepine receptor, involved in tissue repair, was increased in the FR167653-treated groups. At 3 mo, the protective effects of FR167653 were accompanied by a reduction of long-term inflammation process and tubulointerstitial fibrosis development associated with a limitation of ischemia-induced remodeling. This study suggests that such treatment may be useful in protocols aimed at improving the quality of renal transplants from NHBD. In addition, the beneficial role of FR167653 in limiting early injury is associated with secondary reduction in development of tubular atrophy and interstitial fibrosis which are together the hallmark of failing renal transplants. The more efficient effect was observed when FR167653 was added in combination before WI, during cold storage and reperfusion.

Topics: Animals; Cell Adhesion; Enzyme Inhibitors; Fibrosis; Interleukin-1beta; Kidney Diseases; Kidney Transplantation; Kidney Tubules, Proximal; Male; p38 Mitogen-Activated Protein Kinases; Pyrazoles; Pyridines; Receptors, Vascular Endothelial Growth Factor; Reperfusion Injury; Swine; Tumor Necrosis Factor-alpha

Chronic allograft nephropathy (CAN) is the major cause for late graft loss and is therefore a key target for therapy.. The impact of p38 mitogen-activated kinase (MAPK) on CAN was investigated by administering FR167653 (32 mg/kg/day), a specific inhibitor of p38 MAPK, for 4 weeks in addition to conventional cyclosporine therapy (1.5 mg/kg/day for 5 days) in an established experimental rat transplantation model.. Transplanted rats develop glomerulosclerosis, arterial obliteration, interstitial fibrosis and tubular atrophy, all of which are characteristic of CAN, resulting in shortened survival on 32 weeks. However, the inhibition of p38 MAPK by daily subcutaneous treatment with FR167653 resulted in reduced CAN with preserved renal function and prolonged survival. The FR167653-treated rats had fewer phosphorylated p38 MAPK-positive cells in treated kidneys. Concomitantly, the expression of monocyte chemoattractant protein-1/CCL2 and transforming growth factor-beta(1) was markedly reduced.. These results suggest that p38 MAPK phosphorylation is involved in the pathogenesis of CAN and provide evidence that p38 MAPK is a novel, appealing therapeutic target for combating CAN.

Topics: Animals; Graft Survival; Kidney Diseases; Kidney Transplantation; Male; p38 Mitogen-Activated Protein Kinases; Pyrazoles; Pyridines; Rats; Rats, Inbred F344; Rats, Inbred Lew; Treatment Outcome

Hemorrhagic shock has been reported to induce renal dysfunction as a consequence of different kinds of local inflammatory response. p38 mitogen-activated protein kinase (MAPK) is a key mediator in organ dysfunction relating to the inflammatory states, and acts as an important mediator in the intracellular signal pathway for proliferation, differentiation, and production of proinflammatory cytokines such as TNF-alpha and IL-1beta. The effect of p38 MAPK on the hemorrhagic damage has not been clearly estimated as yet. In this study, our aim was to evaluate the role of p38 MAPK on the renal damage during the first 5 h after a hemorrhage using a specific inhibitor of p38 MAPK activation, FR167653. p38 MAPK activation increased immediately after a hemorrhage and decreased with time. renal mRNA expression of TNF-alpha and IL-1beta increased, renal dysfunction continued to progress, and histological inflammatory injuries were confirmed after hemorrhagic shock. With the pretreatment of FR167653, all of these hemorrhagic changes were attenuated, although the induction of the primary hypotensive state was confirmed. This study demonstrated that renal p38 MAPK is activated in hemorrhagic shock, promotes the expression of proinflammatory cytokines in the kidney, and consequently develops renal dysfunction. We concluded that p38 MAPK activation is essential in causing renal damage and that the inhibition of p38 MAPK activation blocks the development of the renal dysfunction after hemorrhagic shock.

Topics: Animals; Blood Urea Nitrogen; Blotting, Western; Cytokines; Hemorrhage; Immunohistochemistry; Inflammation; Interleukin-1; Kidney; Kidney Diseases; Male; Neutrophils; p38 Mitogen-Activated Protein Kinases; Pyrazoles; Pyridines; Rats; Rats, Wistar; RNA, Messenger; Shock, Hemorrhagic; Time Factors; Tumor Necrosis Factor-alpha

Mild haemorrhage occasionally causes delayed death following failure of kidney or multiple organs, but the precise mechanisms have not yet been identified. We investigated the role of tumour necrosis factor-alpha (TNF-alpha), known as a major pro-inflammatory cytokine that leads to multiple organ failure, on the renal damage induced by mild haemorrhage. A mild haemorrhagic state was induced in male anaesthetized rats by bleeding via a common carotid catheter for 20 min at 16.7% of total body blood, 1.09 ml/100 g body weight, without fluid resuscitation. Mean arterial pressure and heart rate decreased soon after haemorrhaging but returned to baseline level up to 5 h after bleeding. TNF-alpha mRNA expression in the kidney and serum TNF-alpha levels were highest at 1 h after bleeding. Intraperitoneal pretreatment with FR167653, an inhibitory compound of TNF-alpha production, as well as of interleukin (IL)-1beta, significantly inhibited the increase in TNF-alpha. The inflammatory cell infiltration and tubular cell injury induced by haemorrhage were suppressed, and the renal dysfunction was dramatically improved by the FR167653 treatment. The morphological changes were also less in the treated group than in those that had not been treated. TNF-alpha has been reported to have striking effects on IL-1beta release and activation of neutrophils, and to play a pivotal role in the expression of the other pro-inflammatory cytokines. Our data show that endogenously-derived TNF-alpha does play a key role in the renal dysfunction during mild haemorrhage. These results should be useful to forensic pathologists to explain the pathogenesis of renal dysfunction induced by a mild haemorrhage and to identify the cause of death where there are no significant morphological changes after mild haemorrhage.

Topics: Animals; Blood Pressure; Heart Rate; Hemorrhage; Immunosuppressive Agents; Interleukin-1; Kidney; Kidney Diseases; Kidney Tubules; Male; Neutrophils; Pyrazoles; Pyridines; Rats; Rats, Wistar; RNA, Messenger; Tumor Necrosis Factor-alpha