Biomedical subjects

Akira Mima

Publications and source records attributed to Akira Mima.

4 recordsLinked to original sources

PubMed2006

Angiotensin II-dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy.

Angiotensin II (Ang II) is known to play a pivotal role in the development of diabetic nephropathy. However, the precise mechanism of Ang II-mediated effects on diabetic nephropathy is still unknown. We have reported that Smad1 plays a key role in diabetic mesangial matrix expansion and directly regulates the transcription of type IV collagen (Col4) in vitro and in vivo. Here we examined the effect of Ang II on the expression of Smad1 and mesangial matrix expansion in streptozotocin (STZ)-induced diabetic rats in vivo, using Ang II type 1 receptor blocker, olmesartan. We also examined the signaling mechanism by which Ang II induces mesangial matrix expansion in vitro. Treatment of diabetic rats with low-dose olmesartan for 20 weeks reduced albuminuria and hyperfiltration without affecting blood pressure and inhibited mesangial matrix expansive changes and the expression of Col4 and smooth muscle alpha actin compared with those in untreated rats. Immunohistochemical staining and Western blotting showed that the increased expression of Smad1, phospho-Smad1, and phospho-Src was inhibited by olmesartan. Ang II induced Col4 synthesis and increased expression of phospho-Src and phospho-Smad1 in cultured mesangial cells, which was blocked by olmesartan. PP2, a Src tyrosine kinase inhibitor, and overexpression of dominant negative Src also reduced the phosphorylation of Smad1. Moreover, addition of small-interfering RNA against Src significantly reduced the phosphorylation of Smad1 and synthesis of Col4. Taken together, these results indicate that Ang II can regulate the development of mesangial matrix expansion in the early phase of diabetic nephropathy through Src and Smad1.

Angiotensin II↗

PubMed2006

Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy.

Diabetic nephropathy is the leading cause of end-stage renal disease, and glomerular mesangial matrix expansion is the hallmark in diabetic nephropathy. However, the precise mechanism for the development of mesangial matrix expansion has remained unknown. The key component involved in mesangial matrix expansion is type IV collagen (Col4). Recently, we have reported that Smad1 transcriptionally regulates expression of Col4 under diabetic conditions in vitro. Here we show that this direct regulator of Col4 also plays a crucial role for mesangial matrix expansion in vivo. Streptozotocin-induced diabetic rats are the model of incipient diabetic nephropathy, and showed various levels of mesangial matrix expansion at 24 weeks. The glomerular expression of Smad1 was significantly increased in diabetic rats with more mesangial matrix expansion by Western blot and immunohistochemical analysis. Furthermore, the glomerular expression of Smad1 was closely correlated with the glomerular expression of Col4 and smooth muscle alpha actin (alpha-SMA), while albuminuria or glomerular filtration rate was not correlated with mesangial matrix expansion. We also found that urinary excretion of Smad1 was closely associated with the severity of mesangial matrix expansion. In cultured mesangial cells expression of Smad1 upregulated the transcriptional activity of key molecules in mesangial matrix expansion, such as Col4 and alpha-SMA. These data indicate the critical involvement of Smad1 in mesangial matrix expansion in the early phase of diabetic nephropathy. Our data imply that urinary Smad1 might be a representative diagnostic marker for mesangial matrix expansion in diabetic nephropathy.

Actins↗

PubMed2005

Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy.

BACKGROUND: We have already reported Gas6 is involved in glomerular hypertrophy observed in diabetic nephropathy. However, the molecular mechanisms involved in glomerular hypertrophy are still unknown, especially in vivo. METHODS: In vivo, diabetes was induced in rats and mice by streptozotocin (STZ) and the activation of the Akt/mTOR pathway in glomeruli was examined. In vitro, mesangial hypertrophy was assessed by [(3)H]leucine incorporation and measuring cell areas. RESULTS: Akt, p70 S6 kinase, and 4E-BP-1 were induced and phosphorylated in rat glomerular lysates after 12 weeks of STZ injection when mesangial and glomerular hypertrophy was observed. We then examined the role of Gas6 by treating STZ-rats with warfarin, and found that warfarin treatment inhibited the phosphorylation of these molecules as well as the hypertrophy. We next examined whether high glucose stimulation can induce the expression of Gas6/Axl in mesangial cells. Stimulation of the cells with 25 mmol/L of glucose increased the expression of Gas6/Axl and mesangial cell size compared with that with 5.6 mmol/L of glucose. This hypertrophic effect was abolished in mesangial cells derived from Gas6 knockout mice. We also found that LY294002 and rapamycin blocked Gas6-induced activation of the Akt/mTOR pathway and mesangial hypertrophy. Furthermore, less phosphorylated Akt-positive or 4E-BP-1-positive areas were found in STZ-treated Gas6 knockout mice than in STZ-treated wild-type mice. CONCLUSION: Our study indicates that the Akt/mTOR pathway is a key signaling cascade in Gas6-mediated mesangial and glomerular hypertrophy and revealed a crucial role of Gas6/Axl and the Akt/mTOR pathway in the development of diabetic nephropathy.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Peritoneal equilibration test at home.

The peritoneal equilibration test (PET) has been widely used as a standardized means for estimating solute transport. However, the procedure is rather complex, and patients must spend more than half a day in the hospital. The fast PET is an alternative method, but the results are not reliable in patients whose peritoneal catheters drain poorly. We postulated that patients could perform the PET at home if educated well about the procedure. To that purpose, we prepared three types of visual aids that introduce the PET procedure: a VCR tape, a DVD disc, and a brochure with photographs. Equilibration tests were performed using the twin-bag system. For making fluid level indicator lines (200 mL and 10 mL), patients are given a guide sheet on which the fresh dialysate bag is placed. After an 8- to 12-hour overnight dwell, the dwelled dialysate is drained completely into the empty bag. Immediately after the patient infuses 2 L of fresh 2.5% glucose dialysis solution, 200 mL of that solution is drained into the bag on which the two fluids levels were previously marked. After mixing, about 190 mL of the dialysate is re-infused, and the remaining 10 mL (the amount indicated by a guide mark at the corner) is left within the bag. After a 4-hour dwell, the dialysate is completely drained into another twin-bag. A standard PET was also performed on a different day, and the data were compared with those from the home PET. Significant correlations were seen in D/D0 and in drain volume between the home PET and the standard PET (n = 10; D/D0: 0.385 +/- 0.054 vs. 0.371 +/- 0.052 respectively, r = 0.872, p = 0.0004; drain volume: 2340 +/- 123 mL vs. 2372 +/- 90 mL respectively, r = 0.788, p = 0.0048). We conclude that the home PET is a clinically useful alternative to the standard PET, saving time and labor while maintaining accuracy.

Adult↗