Inactivation of MAP3K7 in FOXD1-expressing cells results in loss of mesangial PDGFRB and juvenile kidney scarring

Transforming growth factor-beta (TGF beta) plays a central role in renal scarring, controlling extracellular matrix deposition by interstitial cells and mesangial cells. TGF beta signals through Smad and mitogen-activated protein kinase (MAPK) pathways. To understand the role of MAPK in interstitial and mesangial cells, we genetically inactivated TGF beta-activated kinase-1 (Map3k7) using Foxd1(+/cre). Embryonic kidney development was unperturbed in mutants, but spontaneous scarring of the kidney ensued during the first postnatal week, with retention of embryonic nephrogenic rests and accumulation of collagen IV in the mesangium. MAPK signaling in the mesangium of mutant mice was skewed, with depressed p38 but elevated c-Jun NH2-terminal kinase (JNK) activation at postnatal day 3. Despite normal expression of platelet-derived growth factor receptor-beta (PDGFR beta) in the mesangium of mutants at birth, expression was lost concomitantly with the increase in JNK activation, and studies in isolated mesangial cells revealed that JNK negatively regulates Pdgfr beta. In summary, we show that MAP3K7 balances MAPK signaling in mesangial cells, suppressing postnatal JNK activation. We propose that the balance of MAPK signaling is essential for appropriate postnatal regulation of mesangial PDGFR beta expression.