期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 315, 期 2, 页码 F336-F344出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00493.2017
关键词
glomerulosclerosis; kidney development; mesangial cell; TGF beta
资金
- National Institutes of Diabetes and Digestive and Kidney Disease (NIDDK) [R01 DK-078161]
- American Heart Association
- National Institutes of General Medicine (NIGM) [P30 GM-106391]
- NIGM [P30 GM-106391, P20 GM-121301, P20 GM-103392, P30 GM-103392]
- Hematology Core of The Jackson Laboratory
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK078161] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P30GM103392, P20GM121301, P30GM106391] Funding Source: NIH RePORTER
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.
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