ERK and p38 MAP kinase are required for rat renal development

ERK and p38 MAP kinase are required for rat renal development.BackgroundWe previously demonstrated that extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein (MAP) kinase (p38) are strongly expressed in the embryonic kidney. In the present study, we investigated the role of ERK and p38 during kidney development.MethodsRat metanephroi were cultured from 15-day-old embryos, and exposed to inhibitors of MEK, an activator of ERK, PD98059 (300 μmol/L), U0126 (10 μmol/L), or a p38 inhibitor SB203580 (30 μmol/L) 24 to 120 hours after the start of culture. Growth of metanephroi was measured by surface area and thymidine incorporation. Ureteric buds and glomeruli were identified by labeling with Dolichos biflorus lectin and peanut agglutinin, respectively. PCNA staining and TUNEL assay were performed on kidney sections. The level of apoptosis was evaluated by examining DNA ladder formation.ResultsGrowth of metanephroi was significantly inhibited by SB203580 but not by PD98059 or U0126. Ureteric bud branching was not affected by SB203580 or MEK inhibitors. Glomerular number was markedly reduced by SB203580 and to a lesser extent by U0126 (14 ± 2 and 48 ± 10% of controls, respectively). On histological examination, the number of tubuloglomerular structures was reduced in MEK inhibitor-treated metanephroi compared to controls. Very few mesenchymal condensates were observed in kidneys incubated with SB203580. PCNA-positive cells were reduced in SB203580-treated metanephroi compared to control and PD98059-treated kidneys. Apoptosis was increased in SB203580-treated kidneys and to a lesser extent in PD98059-treated cultures.ConclusionsBoth ERK and p38 are required for renal development. ERK appears to play a role in nephrogenesis and p38 for kidney growth and nephrogenesis

BMP7 dose‐dependently stimulates proliferation and cadherin‐11 expression via ERK and p38 in a murine metanephric mesenchymal cell line

BMP7 is expressed in ureteric buds and cap mesenchyme of the fetal kidney, mediating branching morphogenesis and survival and priming of metanephric mesenchyme. Although dose‐dependent effects of BMP7 in collecting duct cells have been reported, studies in metanephric mesenchymal cells are lacking. We examined the effects of BMP7 on MAP kinase activation, proliferation, and expression of cadherins in a metanephric mesenchymal cell line MS7 by thymidine incorporation, immunoblot analysis, and quantitative real‐time PCR. The levels of phosphorylated ERK (P‐ERK) and phosphorylated p38 (P‐p38) were not altered at 10 min, 1 h, and 6 h with low‐dose BMP7 (0.25 nmol/L), but were increased at 24 h. At 24 h, P‐ERK was increased with low‐dose BMP7, but not by intermediate‐ (1 nmol/L) or high‐dose (10 nmol/L) BMP7, whereas p38 was activated by intermediate‐dose BMP7. Cell proliferation of MS7 was significantly increased by low‐ and intermediate‐dose BMP7 and decreased by high‐dose BMP7. A p38 inhibitor SB203580 5 μmol/L or a MEK inhibitor PD98059 5 μmol/L abolished BMP7‐stimulated proliferation. Expression of cadherin‐11, an adhesion molecule known to promote cell migration and compaction, was upregulated by intermediate‐dose BMP7. BMP7‐induced cadherin‐11 expression was inhibited by cotreatment with SB203580 and PD98059. Finally, in metanephroi cultured with siRNA for cadherin‐11, the number and thickness of cap mesenchyme were reduced. In conclusion, BMP7 exerts differential effects depending on the concentration; it may expand mesenchymal cells in the stroma where BMP7 concentration is low and may upregulate cadherin‐11 promoting condensation around the tip of ureteric buds

Maternal undernutrition aggravates renal tubular necrosis and interstitial fibrosis after unilateral ureteral obstruction in male rat offspring.

Maternal undernutrition is known to reduce glomerular number but it may also affect tubulointerstitium, capillary density, and response to oxidative stress. To investigate whether the latter elements are affected, we examined the response to unilateral ureteral obstruction (UUO), an established model of renal tubulointerstitial fibrosis, in the kidney of offspring from control and nutrient restricted rats. Six-week old male offspring from rats given food ad libitum (CON) and those subjected to 50% food restriction throughout pregnancy (NR) were subjected to UUO for 7 days. Body weight was significantly lower in NR. Systolic blood pressure and blood urea nitrogen increased similarly in CON and NR after UUO. Tubular necrosis in the obstructed kidney, on the other hand, was more extensive in NR. Also, the collagen area, a marker of fibrosis, of the obstructed kidney was significantly increased compared with the contralateral kidney only in NR. Capillary density was decreased similarly in the obstructed kidney of CON and NR compared with the contralateral kidney. Urine nitrate/nitrite, a marker of nitric oxide production, from the obstructed kidney was significantly increased in NR compared with CON. Nitrotyrosine, a marker of nitric oxide-mediated free radical injury, was increased in the obstructed kidney compared with the contralateral kidney in both CON and NR, but the extent was significantly greater in NR. In conclusion, more severe tubular necrosis and fibrosis after UUO was observed in NR, which was thought to be due to increased nitrosative stress

Eosinophilic Cystitis Presented as a Manifestation of Hypereosinophilic Syndrome: A Case Report and Review of the Literature

Background: Hypereosinophilic syndrome (HES) is a group of disorders marked by the sustained overproduction of eosinophils, in which eosinophilic infiltration and inflammatory substance release cause damage to multiple organs. Eosinophilic cystitis (EC) is an inflammatory disorder caused by eosinophilic infiltration of the bladder wall. Although EC is often associated with eosinophilia, it has been rarely reported as a manifestation of HES. We report a case of EC as a primary manifestation of HES. The patient was a 27-year-old male with a history of complete intracardiac repair of tetralogy of Fallot who presented with an acute onset of dysuria accompanied by eosinophilia (7.5 × 103/µl, 60% of white blood cells). Ultrasonography and MRI of the bladder showed a bladder mass, a biopsy of which revealed eosinophilic infiltration and degranulation. Methods: We performed a literature search in PubMed from 2001 to 2012 to find patients with EC who may have had HES. Results: There were 4 patients with HES who had EC including the present case. Of 14 patients reported as EC in whom the eosinophil count was described, 5 had eosinophils of ≥1,500/µl. None of the 5 patients had secondary causes for eosinophilia. Of the 9 patients with definite or probable HES, 7 patients (78%) were male and 5 patients (56%) showed a concomitant eosinophilic gastrointestinal disorder. Conclusion: HES may not be uncommon as the cause of EC. Thorough evaluation and close monitoring are warranted in EC patients with elevated eosinophils