Tubular Cell Specific Mst1/Mst2 Deficiency Leads to Chronic Kidney Disease in Mice
Refereed conference paper presented and published in conference proceedings


摘要The Hippo pathway is a regulator of organ size. The core components of the Hippo pathway consist of Mammalian Ste20-like kinases 1/2 (MST1/2) and their scaffold protein SAV1, large tumor suppressor 1/2 (LATS1/2) and their scaffold proteins MOB1A/1B, and two downstream effectors YAP/TAZ. Several members of the Hippo pathway including SAV1, LATS1/2, and YAP/TAZ have been found to be involved in embryonic kidney development or kidney disease. However, the role of MST1/2 in kidney remains unknown.
Here, we showed for the first time that MST1 was highly expressed in all nephron segments and collecting ducts in mouse kidneys. We therefore generated tubular cell specific Mst1/Mst2 double knockout (dKO) mice by intercrossing floxed Mst1/Mst2 mice with Ksp-Cre transgenic mice. dKO mice showed increased kidney weights starting at 4 weeks of age. Body weights were comparable between WT and dKO mice up to 8 weeks of age. However, dKO mice exhibited a significant body weight loss at 6 months and later stages. Kidney structural abnormality and tubular injuries were seen as early as 4 weeks and aggravated with age, as indicated by immune cell infiltration, tubular cell death, thickening of glomerular basement membrane and tubular basement membrane, cast formation, and increased levels of urinary NGAL, a marker for kidney injury. At 6 months of age and later, protein levels of the fibrotic markers α-SMA, fibronectin 1 and collagen Iα1 were significantly increased in dKO kidneys, and Masson’s trichrome staining showed much more collagen deposition in dKO kidneys, indicating dKO mice developed renal fibrosis. Consequently, renal function was impaired at 6 months and older ages, as shown by increased serum creatinine and blood urea nitrogen (BUN) levels in dKO mice. Moreover, dKO kidneys exhibited increased expression of inflammatory factors and infiltrations of macrophages into the interstitium.
YAP activity was significantly enhanced in dKO kidneys at 4 weeks of age, coupled with increased Ki67-positive tubular cell numbers. By generating Mst1/Mst2/Yap triple knockout (tKO) mice, we found that deletion of Yap restored the kidney weights in dKO mice to WT levels, and also fully rescued the expression of all the inflammatory factors measured except TNFα at 4 weeks of age. Notably, an increase in TNFα was found in dKO kidneys at 2 weeks of age, when YAP was not activated yet. These results suggest that the increased kidney weights and most inflammatory responses observed in tubular Mst1/Mst2 deficient mice are dependent on YAP while TNFα expression is induced via both YAP-dependent and -independent mechanisms.
Collectively, we found tubular Mst1/Mst2 deficiency leads to tubular cell hyperproliferation, inflammation, tubular injury, renal fibrosis, and renal dysfunction, indicating that tubular MST1/2 play important roles in restraining renal overgrowth and inflammation and maintaining normal tubular structure and function.
著者XU Chunhua, WANG Yang, WANG Li, LI Wenling, MAK King Lun Kingston, HUANG Yu, XIA Yin
會議名稱The 9th Xiamen Winter Symposium on The Hippo Signaling Pathway in Development & Disease
會議地點Wanda Realm Xiamen North Bay Hotel, Xiamen, P.R.China

上次更新時間 2019-15-01 於 17:18