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Tomohiro Tanaka

Publications and source records attributed to Tomohiro Tanaka.

At least 19 recordsLinked to original sources
PubMed2026

Endoscopic Ultrasound-Guided Versus Transjugular Portal Pressure Measurements: Systematic Review and Meta-Analysis.

PURPOSE: Published reviews of endoscopic ultrasound-guided portal pressure gradient (EUS-PPG) have emphasized feasibility and safety. We performed a systematic review and meta-analysis specifically to evaluate how closely EUS-based portal pressure measurements track invasive comparator measurements in prospective paired studies and to summarize agreement, technical success, and adverse events. METHODS: We searched major databases through January 2026 for prospective cohorts reporting same-patient EUS-based portal pressure measurement and invasive hemodynamic measurements. Correlations were pooled with random-effects models and analyzed separately for studies comparing EUS-PPG with hepatic venous pressure gradient (HVPG) and studies comparing EUS-based portal measurements with direct portal venous pressure. Agreement and threshold discordance were summarized descriptively. RESULTS: Six prospective cohorts (127 attempted procedures) were included. In studies using HVPG as the comparator, the pooled correlation was 0.82 (95% CI, 0.72-0.89; I2 = 0%). In studies comparing EUS-based portal measurements with direct portal venous pressure, the pooled correlation was 0.86 (95% CI, 0.72-0.93; I2 = 16.9%). Technical success was 95.3%. EUS-PPG-attributed adverse events occurred in 2.4% of procedures, with no procedure-related deaths. Agreement data were limited. Reported limits of agreement were wide (approximately - 6 to + 7 mmHg), and discrepancies of 5 mmHg or greater occurred in 4 of 30 paired measurements. CONCLUSIONS: EUS-based portal pressure measurement is feasible and shows a strong association with invasive hemodynamic comparators, but the evidence base remains small (six cohorts, 127 attempted procedures). Further study will be necessary to establish patient-level agreement, procedural reproducibility, EUS-specific clinically significant portal hypertension thresholds, and whether HVPG-based decision thresholds can be transferred to EUS-derived measurements.

Humans↗
PubMed2026

Quantitative proteomic profiling of neural cells-specific metabolic reprogramming in response to mitochondrial dysfunction using iMPAQT2.

Age-related mitochondrial dysfunction is increasingly recognized as a key contributor to neurodegenerative disease pathogenesis. In the central nervous system, neurons, oligodendrocytes, and astrocytes which derived from neural stem cells, fulfill distinct metabolic and functional roles. However, the specific vulnerabilities of these cell types to mitochondrial impairment remain unclear. In this study, we employed the iMPAQT2 proteomics platform to systematically compare the metabolic profiles of neurons, oligodendrocytes, and astrocytes, and to elucidate the molecular consequences of mitochondrial dysfunction induced by chloramphenicol and oligomycin. Our findings indicate that neurons and oligodendrocytes primarily rely on oxidative phosphorylation (OXPHOS) for ATP production, whereas astrocytes predominantly utilize glycolysis. It is noteworthy that oligodendrocytes exhibited enriched pathways for cholesterol synthesis, fatty acid degradation, and heme catabolism-processes that are critical for myelin maintenance. Treatment with the mitochondrial function inhibitors chloramphenicol or oligomycin reduced the expression of OXPHOS enzymes in all cell types. This reduction was particularly pronounced in oligodendrocytes for glycolysis, cholesterol synthesis, heme degradation, and fatty acid degradation. These results suggest that oligodendrocytes are particularly vulnerable to mitochondrial dysfunction, which may play a pivotal role in the pathogenesis of age-related neurodegenerative disorders.

Animals↗
PubMed2007

Therapeutic potential of the chemokine receptor CXCR4 antagonists as multifunctional agents.

The chemokine receptor CXCR4 possesses multiple critical functions in normal and pathologic physiology. CXCR4 is a G-protein-coupled receptor that transduces signals of its endogenous ligand, the chemokine CXCL12 (stromal cell-derived factor-1, SDF-1). The interaction between CXCL12 and CXCR4 plays an important role in the migration of progenitors during embryologic development of the cardiovascular, hemopoietic, central nervous systems, and so on. This interaction is also known to be involved in several intractable disease processes, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis (RA), and pulmonary fibrosis. It is conjectured that this interaction may be a critical therapeutic target in all of these diseases, and several CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogues, were previously developed in our laboratory as specific CXCR4 antagonists that were identified as HIV-entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents, and anti-RA agents. Cyclic pentapeptides, such as FC131 [cyclo(D-Tyr-Arg-Arg-L-3-(2-naphthyl)alanine-Gly)], were also previously found as CXCR4 antagonist leads based on pharmacophores of T140. This review article describes the elucidation of multiple functions of CXCR4 antagonists and the development of a number of low-molecular weight CXCR4 antagonists involving FC131 analogues and other compounds with different scaffolds including linear-type structures.

Amino Acid Sequence↗
PubMed2006

Bezafibrate regulates the expression and enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes.

A clinically employed antihyperlipidemic drug, bezafibrate, has been characterized as a PPAR(alpha, -gamma, and -delta) pan-agonist in vitro. Recent extended trials have highlighted its antidiabetic properties in humans. However, the underlying molecular mechanism is not fully elucidated. The present study was designed to explore potential regulatory mechanisms of intracellular glucocorticoid reactivating enzyme, 11beta-HSD1 and anti-diabetic hormone, adiponectin by bezafibrate in murine adipose tissue, and cultured adipocytes. Treatment of db/db mice with bezafibrate significantly ameliorated hyperglycemia and insulin resistance, accompanied by a marked reduction of triglyceride and nonesterified fatty acids. Despite equipotent in lipid-lowering effects, another fibrate, fenofibrate, did not show such beneficial effects on glycemic control. Treatment of bezafibrate caused a marked decrease in the mRNA level of 11beta-HSD1 preferentially in adipose tissue of db/db mice (-47%, P<0.05), concomitant with a significant increase in plasma adiponectin level (+37%, P<0.01). Notably, treatment of bezafibrate caused a marked decrease in the mRNA level (-34%, P<0.01) and enzyme activity (-32%, P<0.01) of 11beta-HSD1, whereas the treatment substantially augmented the expression (+71%, P<0.01) and secretion (+27%, P<0.01) of adiponectin in 3T3-L1 adipocytes. Knockdown of 11beta-HSD1 by siRNA confirmed that 11beta-HSD1 acts as a distinct oxoreductase in adipocytes and validated the enzyme activity assays in the present study. Effects of bezafibrate on regulation of 11beta-HSD1 and adiponectin in murine adipocytes were comparable with those in thiazolidinediones. This is the first demonstration that bezafibrate directly regulates 11beta-HSD1 and adiponectin in murine adipocytes, both of which may contribute to metabolically-beneficial effects by bezafibrate.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.

BACKGROUND: Lack of leptin is implicated in insulin resistance and other metabolic abnormalities in generalized lipodystrophy; however, the efficacy, safety, and underlying mechanisms of leptin-replacement therapy in patients with generalized lipodystrophy remain unclear. METHODS: Seven Japanese patients with generalized lipodystrophy, two acquired and five congenital type, were treated with the physiological replacement dose of recombinant leptin during an initial 4-month hospitalization followed by outpatient follow-up for up to 36 months. RESULTS: The leptin-replacement therapy with the twice-daily injection dramatically improved fasting glucose (mean +/- SE, 172 +/- 20 to 120 +/- 12 mg/dl, P < 0.05) and triglyceride levels (mean +/- SE, 700 +/- 272 to 260 +/- 98 mg/dl, P < 0.05) within 1 wk. The leptin-replacement therapy reduced insulin resistance evaluated by euglycemic clamp method and augmented insulin secretion at glucose tolerance test with different responses between acquired and congenital types. Improvement of the fatty liver was also observed. The efficacy and safety of the once-daily injection were comparable to those of the twice-daily injection. The leptin-replacement therapy ameliorated macro- and microalbuminuria and showed no deterioration of neuropathy and retinopathy of these patients. The leptin-replacement therapy is beneficial to diabetic complications and lipodystrophic ones. Two patients developed antileptin antibodies but not neutralizing antibodies. The therapy was well tolerated, and its effects were maintained for up to 36 months without any notable adverse effects such as hypoglycemia, high blood pressure, or reduction of bone mineral density. CONCLUSIONS: The present study demonstrates the efficacy and safety of the long-term leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.

Adolescent↗
PubMed2006

Successful 40-hour preservation of the canine small intestine with the cavitary 2-layer method with glutamine supplementation.

BACKGROUND: We recently reported that the cavitary 2-layer method (cTLM) allowed stable 24-hour preservation of canine intestine. The aim of this study was to examine the possibility of the 40-hour preservation by cTLM that is supplemented with glutamine. METHODS: Canine jejunal segments (40 cm) were allotransplanted heterotopically without storage (group 1), after 40-hour cold storage with University of Wisconsin solution (group 2), cTLM (group 3), UW with 2% glutamine (group 4), or cTLM with 2% glutamine (group 5). Mucosal glutamine, histidine, tryptophan, glutathione, and adenosine triphosphate concentrations were determined immediately after preservation. At day 7 after the transplantation, maltose absorption test and histopathologic analysis were performed. RESULTS: Mucosal glutamine concentrations increased significantly with glutamine supplementation during preservation in groups 4 and 5 (P < .01). Mucosal adenosine triphosphate levels in cTLM groups (groups 3 and 5) were similar to those in group 1; group 4 showed very low levels after preservation, despite glutamine supplementation. Mucosal glutathione did not differ among groups 2, 3, 4, and 5 and were significantly lower than in group 1. In the absorption test, serum glucose curves showed a peak level by 30 minutes in groups 1 and 5; delayed peaks were seen in groups 2, 3, and 4 compared with group 1. The villous heights were 879, 555, 685, 688, and 773 microm in groups 1, 2, 3, 4, and 5, respectively (group 1 vs group 2, 3, and 4: P < .05). CONCLUSION: cTLM that was supplemented with glutamine extended a safe preservation period up to 40 hours in canine segmental small intestinal transplantation, although this study failed to elucidate a precise mechanism of the glutamine beneficial effect on the graft mucosa.

Adenosine Diphosphate↗
PubMed2006

[Anesthetic circle system failure caused by a plastic film--a case report].

A 44-year-old woman, ASA I, with breast cancer was scheduled for mastectomy. The anesthetic induction was performed by inhalation of 5% sevoflurane and 66% nitrous oxide in oxygen. After the loss of eyelash reflex assisted ventilation was initiated. At this point, the capnograph indicated inspired carbon dioxide tension of 18mmHg. Anesthetic machine check was soon carried out again. A visual check of non-return valves detected a plastic film, 18 x 21mm large, caught in the expiratory valve. This plastic film impaired complete occlusion of the orifice for the expiratory gas flow. As a result, the patient was rebreathing carbon dioxide. After removing it, the wave form of the capnograph was normalized and end-tidal carbon dioxide tension decreased immediately from 45mmHg to 33mmHg. As we did not detect any foreign matters at the non-return valves on anesthetic machine check before use, the plastic film might have already existed in the disposable corrugated tube before use. The capnograph is a useful device for detecting anesthetic circle system failure in such a case. It is important that the patients' airway is separated from the anesthetic circle system through the use of a filter to prevent foreign matter from being inhaled.

Adult↗
PubMed2005

GPR40 gene expression in human pancreas and insulinoma.

To assess gene expression of a membrane-bound G-protein-coupled fatty acid receptor, GPR40, in the human pancreas and islet cell tumors obtained at surgery were analyzed. The mRNA level of the GPR40 gene in isolated pancreatic islets was approximately 20-fold higher than that in the pancreas, and the level was comparable to or rather higher than that of the sulfonylurea receptor 1 gene, which is known to be expressed abundantly in human pancreatic beta cells. A large amount of GPR40 mRNA was detected in tissue extracts from two cases of insulinoma, whereas the expression was undetectable in glucagonoma or gastrinoma. The present study demonstrates that GPR40 mRNA is expressed predominantly in pancreatic islets in humans and that GPR40 mRNA is expressed solely in human insulinoma among islet cell tumors. These results indicate that GPR40 is probably expressed in pancreatic beta cells in the human pancreas.

Humans↗
PubMed2005

Possibility of islet transplantation from a nonheartbeating donor pancreas resuscitated by the two-layer method.

BACKGROUND: The shortage of cadaveric donors is a problem in islet transplantation, and recent improvements in this field have led to renewed interest in the use of nonheartbeating (NHB) donors. NHB donor pancreata that could provide a significant source for islet transplantation are associated with warm ischemic injury. We tested whether the two-layer method (TL) could improve islet yield and function from damaged pancreata after warm ischemia (WI). METHODS: Lewis rats were divided into six groups. In groups 1 to 3, rats were subjected to 0, 30, and 45 minutes of WI, respectively. Islets were isolated immediately (subgroup a) or after 3-hour preservation with TL (subgroup b). Isolated islets were assessed in terms of islet yield and in vivo function. We also assessed the pancreatic tissue ATP concentration before isolation and distended pancreata morphologically after chemical digestion by H&E staining. RESULTS: Islet yield decreased significantly after 30 minutes of WI in group 2a, whereas TL preservation doubled this decreased yield in group 2b. Forty-five minutes of WI resulted in nearly no islet yield in both groups 3a and 3b. The success rates of transplantation in groups 1a, 1b, 2a, and 2b were 100%, 100%, 0%, and 75%, respectively. Increased tissue ATP levels and alleviation of morphological islet damage were observed in group 2b. CONCLUSIONS: These results demonstrated that pancreata damaged from 30-minute WI were restored by 3-hour TL preservation. TL may allow the selective use of NHB donors as an alternative source for islet transplantation.

Adenosine Triphosphate↗
PubMed2005

CCAAT/enhancer binding protein alpha maintains the ability of insulin-stimulated GLUT4 translocation in 3T3-C2 fibroblastic cells.

In 3T3-L1 preadipocytes, hormonal induction causes adipose conversion and facilitates the expression of insulin-sensitive glucose transporter, GLUT4. Evidence has accumulated that, in 3T3-L1 preadipocytes, the formation of GLUT4 storage vesicle and its translocation to plasma membrane precede both lipid accumulation and expression of GLUT4 and C/EBPalpha, a key transcription factor for adipose differentiation. On the other hand, 3T3-C2 fibroblastic cells, a subline of 3T3-L1, follow adipogenic process till mitotic clonal expansion stage (2 days after hormonal induction), but do not proceed to terminal differentiation stage (8 days after the induction), resulting in a lack of adipose conversion and GLUT4 expression. Here we show that, when myc-tagged GLUT4 was retrovirally expressed in 3T3-C2 cells, insulin-stimulated GLUT4 translocation did occur on day 2 after the induction. On day 8 after the induction, however, neither GLUT4 translocation nor the expression of C/EBPalpha was observed. We also created 3T3-C2 cells stably expressing both myc-tagged GLUT4 and C/EBPalpha, demonstrating that co-expressed cells showed insulin-stimulated GLUT4 translocation on day 8 after the induction, as well as adipose conversion coupling with PPARgamma expression. Our results provide evidence that C/EBPalpha has the potential to maintain the ability of insulin-stimulated GLUT4 translocation in C/EBPalpha-deficient 3T3-C2 fibroblastic cells.

3T3 Cells↗
PubMed2005

Transgenic expression of mutant peroxisome proliferator-activated receptor gamma in liver precipitates fasting-induced steatosis but protects against high-fat diet-induced steatosis in mice.

Steatosis is one of the most common liver diseases and is associated with the metabolic syndrome. A line of evidence suggests that peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma are involved in its pathogenesis. Hepatic overexpression of PPARgamma1 in mice provokes steatosis, whereas liver-specific PPARgamma disruption ameliorates steatosis in ob/ob mice, suggesting that hepatic PPARgamma functions as an aggravator of steatosis. In contrast, PPARalpha-null mice are susceptible to steatosis because of reduced hepatic fatty acid oxidation. PPARgamma with mutations in its C-terminal ligand-binding domain (L468A/E471A mutant PPARgamma1) have been reported as a constitutive repressor of both PPARalpha and PPARgamma activities in vitro. To elucidate the effect of co-suppression of PPARalpha and PPARgamma on steatosis, we generated mutant PPARgamma transgenic mice (Liver mt PPARgamma Tg) under the control of liver-specific human serum amyloid P component promoter. In the liver of transgenic mice, PPARalpha and PPARgamma agonist-induced augmentation of the expression of downstream target genes of PPARalpha and PPARgamma, respectively, was significantly attenuated, suggesting PPARalpha and PPARgamma co-suppression in vivo. Suppression of PPARalpha and PPARgamma target genes was also observed in the fasted and high-fat-fed conditions. Liver mt PPARgamma Tg were susceptible to fasting-induced steatosis while being protected against high-fat diet-induced steatosis. The opposite hepatic outcomes in Liver mt PPARgamma Tg as a result of fasting and high-fat feeding may indicate distinct roles of PPARalpha and PPARgamma in 2 different types of nutritionally provoked steatosis.

Animals↗
PubMed2005

Detailed analysis of mucosal restoration of the small intestine after the cavitary two-layer cold storage method.

Small bowel transplantation (SBT) is associated with a high incidence of infectious complications because of ischemia/reperfusion (I/R) mucosal injury concomitant with potent immunosuppression. In this study, we evaluated whether the cavitary two-layer method (cTLM) could reduce I/R injury and allow early mucosal restoration, particularly after prolonged preservation and transplantation. Canine heterotopic segmental SBT was performed immediately without preservation (group 1), after 24-h preservation in UW solution (group 2) or by the cTLM (group 3). The graft samples were taken 1 h after reperfusion and on days 1, 4 and 7. We assessed graft mucosa with detailed microscopic and electromicroscopic analyses. In Group 3, histological injury and cell apoptosis after transplantation were significantly alleviated and rapidly recovered to a similar level of group 1. The mucosal restoration was morphologically completed within 4 days. In contrast, in group 2, more pronounced mucosal injury and delayed recovery were noted. Crypt cell proliferation activity was well maintained in groups 1 and 3 throughout the experimental period. Our ultrastructural analysis suggested that mitochondrial integrity achieved by the cTLM was a basal mechanism under the prompt mucosal restoration. The cTLM could reduce I/R injury, facilitate mucosal regeneration and restore the nearly normal structure early after SBT.

Animals↗
PubMed2005

Parasympathetic mediated pupillary dilation elicited by lingual nerve stimulation in cats.

PURPOSE: To determine the autonomic efferent nerve pathways for the reflex pupillary dilation elicited by somatic stimulation in cats. METHODS: Cats anesthetized with a mixture of alpha-chloralose (50 mg/kg) and urethane (100 mg/kg) were intubated and paralyzed by intravenous injection of pancuronium bromide. The central cut end of the lingual nerve (LN) was stimulated electrically to simulate somatic stimulation, and 1 microL of lidocaine (2%) was microinjected into the Vsp or the EW nucleus to determine its effect on the pupillary dilation induced by LN stimulation. The effect of electrically stimulating the Vsp or sectioning the superior cervical sympathetic nerve (CSN) on the pupillary response was also examined. RESULTS: Stimulation of the LN or the trigeminal spinal nucleus (Vsp) evoked pupillary dilation in a frequency- and intensity-dependent manner. These responses were not affected by sectioning the ipsilateral or both CSNs. The pupillary responses were markedly suppressed by microinjecting lidocaine into the ipsilateral Vsp or the Edinger-Westphal (EW) nucleus, but not by injection into the contralateral Vsp. CONCLUSIONS: These results indicate that the Vsp and EW nucleus act as bulbar relay centers for pupillary dilation elicited by LN stimulation and suggest that the efferent arc of the response is a parasympathetic pathway. The contralateral pupillary dilation appears to be mediated, at least in part, by fibers projecting from the Vsp to the contralateral EW nucleus.

Animals↗
PubMed2005

Skeletal muscle AMP-activated protein kinase phosphorylation parallels metabolic phenotype in leptin transgenic mice under dietary modification.

Leptin augments glucose and lipid metabolism independent of its effect on satiety. Administration of leptin in rodents increases skeletal muscle beta-oxidation by activating AMP-activated protein kinase (AMPK). We previously reported that, as hyperleptinemic as obese human subjects, transgenic skinny mice overexpressing leptin in liver (LepTg) exhibit enhanced insulin sensitivity and lipid clearance. To assess skeletal muscle AMPK activity in leptin-sensitive and -insensitive states, we examined phosphorylation of AMPK and its target, acetyl CoA carboxylase (ACC), in muscles from LepTg under dietary modification. Here we show that phosphorylation of AMPK and ACC are chronically augmented in LepTg soleus muscle, with a concomitant increase in the AMP-to-ATP ratio and a significant decrease in tissue triglyceride content. Despite preexisting hyperleptinemia, high-fat diet (HFD)-fed LepTg develop obesity, insulin-resistance, and hyperlipidemia. In parallel, elevated soleus AMPK and ACC phosphorylation in regular diet-fed LepTg is attenuated, and tissue triglyceride content is increased in those given HFD. Of note, substitution of HFD with regular diet causes a robust recovery of soleus AMPK and ACC phosphorylation in LepTg, with a higher rate of body weight reduction and a regain of insulin sensitivity. In conclusion, soleus AMPK and ACC phosphorylation in LepTg changes in parallel with its insulin sensitivity under dietary modification, suggesting a close association between skeletal muscle AMPK activity and sensitivity to leptin.

AMP-Activated Protein Kinases↗
PubMed2005

[Role of PPARs in the pathophysiology of nonalcoholoic fatty liver disease].

Pathogenic role of intrahepatic lipid accumulation in insulin resistance and metabolic syndrome has been well documented. Liver steatosis constitutes a risk factor for nonalcoholic steatohepatitis (NASH), one of the leading causes of obesity-related morbidity and mortality. Although pathophysiology of steatosis is multifactorial, a line of evidence from rodent studies suggests that PPARalpha and PPARgamma are involved. PPARalpha is highly expressed in liver and its activation by agonists leads to augmented fatty acid oxidation and protects against steatosis. PPARgamma, which is transcriptionally up-regulated in steatosis, activates lipogenic enzymes and exacerbates steatosis. However, recent human studies have suggested that PPARgamma agonists improve NASH possibly by its primary insulin-sensitizing effect on adipocytes. PPARs modulation is becoming a rational and effective therapeutic approach for the treatment of nonalcoholic fatty liver disease.

Fatty Liver↗
PubMed2004

An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes.

Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property. We thus examined the effect of telmisartan on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of telmisartan effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with telmisartan caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as aP2 and adiponectin. By contrast, telmisartan attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that telmisartan augmented GLUT4 protein expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability.

3T3 Cells↗
PubMed2004

Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy.

Diabetic nephropathy is the leading cause of end-stage renal disease, for which effective therapy to prevent the progression at advanced stages remains to be established. There is also a long debate whether diabetic glomerular injury is reversible or not. Lipoatrophic diabetes, a syndrome caused by paucity of adipose tissue, is characterized by severe insulin resistance, dyslipidemia, and fatty liver. Here, we show that a genetic model of lipoatrophic diabetes (A-ZIP/F-1 mice) manifests a typical renal injury observed in human diabetic nephropathy that is associated with glomerular hypertrophy, diffuse and pronounced mesangial widening, accumulation of extracellular matrix proteins, podocyte damage, and overt proteinuria. By crossing A-ZIP/F-1 mice with transgenic mice overexpressing an adipocyte-derived hormone leptin, we also reveal that leptin completely prevents the development of hyperglycemia and nephropathy in A-ZIP/F-1 mice. Furthermore, continuous leptin administration to A-ZIP/F-1 mice by minipump beginning at 40 weeks of age significantly alleviates the glomerular injury and proteinuria. These findings demonstrate the therapeutic usefulness of leptin at least for a certain type of diabetic nephropathy. The model presented here will serve as a novel tool to analyze the molecular mechanism underlying not only the progression but also the regression of diabetic nephropathy.

Animals↗