p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli

Background The p38 mitogen-activated protein kinase (MAPK) pathway is activ ated by several stress factors, potentially leading to cellular apoptosis a nd growth. Little is known about the pattern of glomerular p38 MAPK pathway activation during the course of diabetic nephropathy (DN). We examined the activity and expression of the p38 MAPK pathway members, p38 MAPK, MKK3/6, cAMP-responsive element binding protein (CREB), and MAPK phosphatase-1 (MK P-1), in experimental DN in rats over the course of four months. Methods, Control (C, N = 16) and diabetic (DM; N = 16) rats were studied. F our rats from each group were sacrificed monthly, and competitive reverse t ranscription-polymerase chain reaction and Western blot were performed with microdissected and sieved glomeruli, respectively. Results. Glomerular p38 MAPK mRNA expression was significantly higher in DM than C (P < 0.01) throughout the four-month period. Western blot revealed an average 3.1-fold increase in p38 MAPK protein throughout the study perio d (P < 0.05). However, p38 MAPK activity was significantly increased only i n one- and two-month diabetic glomeruli, Glomerular MKK3/6 and CREB mRNA as well as activity were significantly increased only in one- and two-month D M compared with C. MKP-1 mRNA showed a similar pattern. Conclusions. Glomerular p38 MAPK activity was increased in early DN. Parall el to this, we also showed, to our knowledge for the first time, that there were increased MKK3/6 and CREB activities and mRNA expression. This activa ted p38 MAPK pathway in diabetic glomeruli may, in part, play a role in the pathogenesis of early hypertrophy and extracellular matrix accumulation.