ERK and p38 MAP kinase are required for rat renal development.
BACKGROUND
We 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.


METHODS
Rat metanephroi were cultured from 15-day-old embryos, and exposed to inhibitors of MEK, an activator of ERK, PD98059 (300 micromol/L), U0126 (10 micromol/L), or a p38 inhibitor SB203580 (30 micromol/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.


RESULTS
Growth 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.


CONCLUSIONS
Both ERK and p38 are required for renal development. ERK appears to play a role in nephrogenesis and p38 for kidney growth and nephrogenesis.
Hida
Mariko
M
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Omori
Sayu
S
Awazu
Midori
M
D000818:Animals; D017209:Apoptosis; D005314:Embryonic and Fetal Development / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004801:Eosine Yellowish-(YS); D015870:Gene Expression; D006416:Hematoxylin; D007668:Kidney / Q000196:embryology*; D007678:Kidney Glomerulus / Q000196:embryology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009924:Organ Culture Techniques; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D014513:Ureter / Q000196:embryology; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D025721:WT1 Proteins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin