Effects of salt supplementation in uninephrectomized KK-Ay mice: Examining the potential of a diabetic kidney disease model.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD). Although current therapeutic strategies for DKD, including sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists, have shown some degree of efficacy, they have failed to completely halt the progression of DKD to ESRD owing to the complexity of DKD pathogenesis. Elucidating the pathophysiological mechanism of DKD is essential for the development of novel therapeutic strategies. In this study, we investigated the pathophysiological characteristics of uninephrectomized (UNx) KK-Ay mice and examined the effects of salt supplementation on the acceleration of renal injury in these mice. UNx KK-Ay mice exhibited pathophysiological renal abnormalities with glomerular and tubulointerstitial fibrosis. Additionally, salt supplementation exacerbated renal injury, particularly tubular injury. These results suggest that UNx KK-Ay mice are useful models for advanced DKD and that salt exacerbates tubular damage in DKD.

JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits significant anti-inflammatory effect while maintaining bone mineral density in mice.

Classic glucocorticoids have been prescribed for various inflammatory diseases, such as rheumatoid arthritis, due to their outstanding anti-inflammatory effects. However, glucocorticoids cause numerous unwanted side effects, including osteoporosis and diabetes. Hence, selective glucocorticoid receptor modulators (SGRMs), which retain anti-inflammatory effects with minimized side effects, are among the most anticipated drugs in the clinical field. The assumption is that there are two major mechanisms of action via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, anti-inflammatory effects of glucocorticoids are largely due to TR, while the side effects associated with glucocorticoids are mostly mediated through TA. We previously reported that JTP-117968, a novel SGRM, maintained partial TR activity while remarkably reducing the TA activity. In this study, we investigated the anti-inflammatory effect of JTP-117968 on a lipopolysaccharide (LPS) challenge model and collagen-induced arthritis (CIA) model in mice. Meanwhile, we tested the effect of JTP-117968 on the bone mineral density (BMD) in mouse femur to evaluate the side effect. Based on the evaluation, JTP-117968 reduced the plasma levels of tumor necrosis factor α induced by LPS challenge in mice significantly. Remarkably, CIA development was suppressed by JTP-117968 comparably with prednisolone and PF-802, an active form of fosdagrocorat that has been developed clinically as an orally available SGRM. Strikingly, the side effect of JTP-117968 on mouse femoral BMD was much lower than those of PF-802 and prednisolone. Therefore, JTP-117968 has attractive potential as a new therapeutic option against inflammatory diseases with minimized side effects compared to classic glucocorticoids.

Conventional and novel impacts of ferric citrate on iron deficiency anemia and phosphorus metabolism in rats.

Ferric citrate is an oral iron-based phosphate binder, being known to affect iron status and improve iron deficiency anemia (IDA) in chronic kidney disease (CKD) patients. We examined whether oral administration of ferric citrate could change iron status and improve anemia without affecting phosphorus metabolism in iron deficiency anemia rats. In Normal rat study, normal rats were fed a diet containing 0.3 or 3% ferric citrate for 11 days for setting the dose and administration period of ferric citrate. The effects of ferric citrate on iron status- and phosphorus metabolism-related parameters were evaluated using blood and urine samples. Next, an iron deficiency anemia was induced by feeding iron-depleted diet in rats. After 7 days of starting the iron-depleted diet, 0.3% ferric citrate was administered for 7 days by dietary admixture. Iron status- and phosphorus metabolism-related parameters were evaluated with blood and urine samples. In Normal rat study, 3% ferric citrate treatment increased serum iron level and transferrin saturation (TSAT), and decreased serum phosphorus level, intact fibroblast growth factor 23 (iFGF23) level, and urinary phosphorus excretion, but 0.3% ferric citrate treatment showed no effects. On the other hand, in Iron deficiency anemia rat study, 0.3% ferric citrate treatment increased iron status-related parameters and improved anemia, but did not show any apparent changes in phosphorus metabolism-related parameters. In conclusion, ferric citrate could have hematopoietic effects without affecting phosphorus metabolism, and could be a potential option for the treatment of IDA in patients without CKD.

JTE-852, a novel spleen tyrosine kinase inhibitor, blocks immunoglobulin G-mediated cellular responses and autoimmune reactions in vivo.

AIMS: Immune and inflammatory responses mediated by immunoglobulin (Ig) G are largely responsible for the pathogenesis of autoimmune diseases. Spleen tyrosine kinase (Syk) plays a pivotal role in the IgG-mediated responses; therefore, Syk has emerged as a new therapeutic target for the treatment of autoimmune diseases. In this study, we investigated the inhibitory actions of JTE-852, a novel Syk inhibitor, on IgG-mediated cellular responses and autoimmune reactions in vivo. MAIN METHODS: We examined mediator secretion from human monocytes. We also conducted rat models of reversed cutaneous anaphylaxis (RCA) and reversed passive Arthus (RPA), which are classified as type II and type III hypersensitivities, respectively. In a rat collagen-induced arthritis (CIA) model, JTE-852 or methotrexate was administered preventively (before the onset of arthritis) or therapeutically (after the onset of arthritis). KEY FINDINGS: JTE-852 blocked secretion of reactive oxygen species and tumor necrosis factor-α from monocytes stimulated by IgG crosslinking. In the RCA and RPA models, JTE-852 also suppressed edema and dye leakage, respectively. In the CIA model, JTE-852 showed both preventive and therapeutic effects against joint swelling and bone erosion; on the other hand, methotrexate did not show the therapeutic effect. SIGNIFICANCE: JTE-852 attenuates IgG-mediated responses and signs in animal model of autoimmune diseases. JTE-852 is thus a promising candidate for a novel, orally available drug for the treatment of autoimmune diseases.

Pharmacological effects of JTT-551, a novel protein tyrosine phosphatase 1B inhibitor, in diet-induced obesity mice.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin signaling as well as insulin signaling. JTT-551 is a new PTP1B inhibitor, which is reported to improve glucose metabolism by enhancement of insulin signaling. We have evaluated an antiobesity effect of JTT-551 using diet-induced obesity (DIO) mice. A single administration of JTT-551 was provided to DIO mice with or without leptin, and DIO mice were given food containing JTT-551 for six weeks. A single administration of JTT-551 with leptin treatment enhanced the food inhibition and the signal transducer and activator of transcription 3 (STAT3) phosphorylation in hypothalamus. Moreover, chronic administration of JTT-551 showed an antiobesity effect and an improvement of glucose and lipid metabolism in DIO mice. JTT-551 shows an antiobesity effect possibly by enhancement of leptin signaling and could be useful in the treatment of type 2 diabetes and obesity.

Inhibitory effect of SPE-39 due to tyrosine phosphorylation and ubiquitination on the function of Vps33B in the EGF-stimulated cells.

Although SPE-39 is a binding protein to Vps33B that is one of the subunit in the mammalian HOPS complex, the elements of SPE-39 function remain unknown. Here, we show that tyrosine phosphorylation of SPE-39 following EGF stimulation plays a role in the stability of SPE-39 itself. Ubiquitination of the C-terminal region of SPE-39 was also elevated in response to EGF stimulation, and this process was regulated by the phosphorylation of Tyr-11 in SPE-39. However, association of Vps33B with SPE-39 inhibited the elevation of ubiquitination of SPE-39 following EGF stimulation, which might be responsible for the stabilization of SPE-39. Furthermore, an opposing functional relationship between SPE-39 and Vps33B on the downregulation of the EGF receptor was observed in EGF-stimulated COS-7 cells.

Increased fat absorption and impaired fat clearance cause postprandial hypertriglyceridemia in Spontaneously Diabetic Torii rat.

In diabetes, postprandial hyperlipidemia is recognized as a risk factor for premature atherosclerosis and following cardiovascular disease. In the present study, features of fat absorption and clearance were examined to clarify the lipid metabolism of Spontaneously Diabetic Torii (SDT) rats. Olive oil was orally administered to evaluate increase of blood triglyceride (TG) level. Mesenteric lymph chylomicron TG was also measured. mRNAs of enzymes and transfer protein related to TG metabolism and histopathological changes were evaluated. In an oil loading test, elevation of TG in plasma and lymph chylomicron was increased in SDT rats. Interestingly, SDT rats showed elevation of plasma TG after oil loading and relatively low epididymal fat lipoprotein lipase (LPL) mRNA expression even at the pre-diabetic state without increase of TG absorption from intestine. In the diabetic state, intestines of SDT rats were hypertrophic and expressed mRNAs of enzymes and transfer protein related to TG absorption highly. From these results, it seems that intestinal abnormalities related to hypoinsulinemia/hyperglycemia cause postprandial hypertriglyceridemia in SDT rats. In addition, our findings suggest that SDT rats have impaired lipid catabolism antecedent to hypoinsulinemia/hyperglycemia. These characteristics of SDT rats can be useful in studies of diabetic hypertriglyceridemia and TG metabolism.