The expression of mitogen-activated protein kinases (MAPK) in DBA/2-pcy/pcy (pcy) mice, a murine model of polycystic kidney disease was investigated. Proliferating cell nuclear antigen-positive cells were recognized in cyst epithelium from embryonic day 14.5 to 25 wk of age. Extracellular signal-regulated kinase (ERK) was expressed in the renal tubules of control and pcy mice, but stronger immunostaining was observed in cyst epithelium. Phosphorylated ERK was detected only in pcy mice and was localized predominantly in the cysts. p38 MAPK (p38) was no longer expressed after birth in controls but was detected in the cyst epithelium and in occasional tubular cells of pcy mice at all stages examined. c-Jun N-terminal kinase (JNK) was expressed in all tubular segments of controls after neonatal day 7, whereas in pcy kidneys, tubules became positive for JNK after 8 wk, and the cysts expressed little JNK. Administration of an oral MAP/ERK kinase inhibitor, PD184352, 400 mg/kg per d, to 10-wk-old pcy mice daily for the first week and then every third day for 6 additional weeks significantly decreased BP, kidney weight, serum creatinine level, and water intake and significantly increased urine osmolality. The cystic index and expression of phosphorylated ERK and ERK were significantly lower in PD184352-treated pcy mice. These results demonstrate that the expression of MAPK is dysregulated in cyst epithelium and that inhibition of ERK slowed the progression of renal disease in pcy mice.

We investigated the expression of ERK, p38 mitogen-activated protein kinase (p38), and JNK in renal tubules of diabetic rats following 3 wk after streptozotocin injection (DM). Although the expression of ERK was not different between controls and DM, phosphorylated ERK was expressed more intensely in DM. p38 And phosphorylated p38 were detected only in the diabetic kidney and were localized in all tubular segments. JNK and phosphorylated JNK were expressed similarly in controls and DM. Transforming growth factor (TGF)-beta was expressed in all tubular segments of DM, coinciding with the localization of p38. In LLC-PK1 cells, phosphorylation of ERK and p38 increased after 24- to 72-h exposure to high glucose (HG). Coincubation with a p38 inhibitor SB-203580 or a MEK inhibitor, PD-98059, suppressed the HG-induced increases in protein content, [3H]leucine incorporation, and the protein-to-DNA ratio. SB-203580 or PD-98059 also abolished the HG-stimulated expression of TGF-beta protein. These results demonstrate that ERK and p38 are activated in renal tubular cells of DM and may mediate HG-induced cellular hypertrophy and TGF-beta expression.

Abstract. Cyclin kinase inhibitor p27 Kip 1

. Combination therapy with PPAR␥ and PPAR␣ agonists increases glucose-stimulated insulin secretion in db/db mice. Am J Physiol Endocrinol Metab 284: E966-E971, 2003; 10.1152/ ajpendo.00149.2002.-Although peroxisome proliferator-activated receptor (PPAR)␥ agonists ameliorate insulin resistance, they sometimes cause body weight gain, and the effect of PPAR agonists on insulin secretion is unclear. We evaluated the effects of combination therapy with a PPAR␥ agonist, pioglitazone, and a PPAR␣ agonist, bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J mice and db/db mice, and we investigated glucose-stimulated insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight gain in db/db mice was less with KRP-297 treatment than with pioglitazone or pioglitazone ϩ bezafibrate treatment. Plasma glucose, insulin, triglyceride, and nonesterified fatty acid levels were elevated in untreated db/db mice compared with untreated C57BL/6J mice, and these parameters were significantly ameliorated in the PPAR␥ agonist-treated groups. Also, PPAR␥ agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPAR␥ and -␣ agonists. We conclude that combination therapy with PPAR␥ and PPAR␣ agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.peroxisome proliferator-activated receptor; glucose-stimulated insulin secretion; glucolipotoxicity; insulin resistance; type 2 diabetes with obesity PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)␥ agonists have been used for the treatment of type 2 diabetic patients, especially those with obesity, all over the world. They ameliorate insulin resistance of peripheral tissues, such as skeletal muscle, liver, and adipocytes, by various suggested mechanisms. Although some literature has suggested effects of PPAR␥ agonists on the pancreas (13, 32), only a few studies have investigated this issue (23,29,30). Because the expression of PPAR␥ is confirmed not only in rodent (1) but also in human islets (5), an effect of PPAR␥ agonists on the pancreas has been suggested.On the other hand, fibrates are PPAR␣ agonists and have been used for patients with dyslipidemia. Some literature has reported that PPAR␣ agonists also ameliorated insulin resistance (6,7,14,19,24,28,36), but the effect on insulin secretion is unclear. Dual agonists of PPAR␥ and -␣, 25,26) and , have been developed, and their utility for diabetes and/or metabolic syndrome has been suggested. However, studies of combination therapy with a PPAR␥ agonist and a PPAR␣ agonist are rare (2, 21), and their effect on insulin secretion has not been reported.We hypothesized that combination therapy with PPAR␥ and -␣ agonists would be useful for reducing lipotoxicity (10, 20, 37) in type 2 diabetes with obesity by augmenting the lipid-lowering effects. We used the PPAR␥ agonist pioglitazone (PIO), combination therapy with the PPAR␥ agonist PIO and the PPAR␣ agonist bezabibrate (P...

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