Reduction of functioning nephron number stimulates increased protein synthesis in the remaining nephron segments, particularly the proximal tubule, leading to increased cell size and mass but not cell number. This type of growth is termed compensatory renal hypertrophy (CRH). CRH occurs not only after surgical renal ablation (secondary to cancer, extremely injured or diseased kidney, or as a kidney donor) but also in virtually all kidney diseases that cause nephron damage and consequently a reduction in the number of functioning nephrons. CRH may actually be a maladaptive response and has been increasingly implicated in fostering further nephron damage, interstitial fibrosis, tubular atrophy and progressive decline of renal function, ultimately leading to end-stage renal disease (ESRD). To date, however, the molecular signals and signaling mechanisms mediating the increased protein synthesis that underlies CRH remain unclear. We have recently reported that CRH is mediated by activation of the mammalian target of rapamycin (mTOR), a central regulator of protein synthesis and cell size control. Our recent preliminary studies revealed that the mTOR signaling activity in renal proximal tubule cells is very sensitive to amino acid load in that amino acid loads activated mTOR signaling within 1 min. Furthermore, we also observed that amino acids activated hVPS34 (the homologue of yeast vacuolar protein sorting defective 34 in mammalian cells) in renal proximal tubule cells. Moreover, our in vivo experiments with mice revealed dramatic activation of hVps34 in the remaining kidney in response to removal of contralateral kidney. In addition, our preliminary data indicate that renal blood flow and free amino acid content are both increased significantly in the remaining kidney as an early response to contralateral nephrectomy. Based on these observations, the specific hypothesis behind the proposed research is that increased delivery of amino acids to the remaining nephron is a growth stimulus that activates hVPS34-dependent mTOR signaling as a major regulatory pathway mediating increased protein synthesis, resulting in CRH. Our long-term objectives are to elucidate the regulatory pathways controlling development of CRH and their potential relationship with progressive renal injury. Our proposed studies for this very first R01 application from a new investigator will have three specific aims for the 5 year time period:
Specific Aim #1 will test our hypothesis that following reduction of functioning nephron number, increased delivery of amino acids to the residual functioning nephrons provides a growth stimulus to initiate CRH.
Specific Aim #2 is to investigate the role of the 40S ribosomal protein S6 in renal hypertrophy.
Specific Aim #3 will identify the upstream mediator of mTOR activation that regulates CRH.
Loss of functioning nephrons stimulates hypertrophic growth of the residual functioning nephrons. This kidney response is known as compensatory renal hypertrophy (CRH). CRH has been increasingly implicated in fostering further nephron damage and progressive decline of renal function, leading to end-stage renal disease (ESRD) but the initial growth signal(s) and molecular signaling mechanism(s) mediating increased protein synthesis that underlies CRH remain unknown. We propose to use combined in vivo and in vitro studies to investigate both upstream and downstream of mTOR activation in CRH.
|Wu, Huijuan; Chen, Jianchun; Xu, Jinxian et al. (2016) Blocking rpS6 Phosphorylation Exacerbates Tsc1 Deletion-Induced Kidney Growth. J Am Soc Nephrol 27:1145-58|
|Chen, Jian-Kang; Nagai, Kojiro; Chen, Jianchun et al. (2015) Phosphatidylinositol 3-kinase signaling determines kidney size. J Clin Invest 125:2429-44|
|Ma, Seong Kwon; Wang, Yinqiu; Chen, Jianchun et al. (2015) Overexpression of G-protein-coupled receptor 40 enhances the mitogenic response to epoxyeicosatrienoic acids. PLoS One 10:e0113130|
|Chen, Jianchun; Chen, Jian-Kang; Harris, Raymond C (2015) EGF receptor deletion in podocytes attenuates diabetic nephropathy. J Am Soc Nephrol 26:1115-25|
|Peng, Jianping; Li, Xiaoning; Zhang, Dongshan et al. (2015) Hyperglycemia, p53, and mitochondrial pathway of apoptosis are involved in the susceptibility of diabetic models to ischemic acute kidney injury. Kidney Int 87:137-50|
|Xu, Jinxian; Chen, Jianchun; Dong, Zheng et al. (2015) Phosphorylation of ribosomal protein S6 mediates compensatory renal hypertrophy. Kidney Int 87:543-56|
|Wei, Qingqing; Dong, Guie; Chen, Jian-Kang et al. (2013) Bax and Bak have critical roles in ischemic acute kidney injury in global and proximal tubule-specific knockout mouse models. Kidney Int 84:138-48|
|Chen, Jianchun; Chen, Jian-Kang; Conway, Edward M et al. (2013) Survivin mediates renal proximal tubule recovery from AKI. J Am Soc Nephrol 24:2023-33|
|Chen, Jianchun; Chen, Mystie X; Fogo, Agnes B et al. (2013) mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking. J Am Soc Nephrol 24:198-207|
|Chen, Jian-Kang (2013) PIK3C3/VPS34, the class III PtdIns 3-kinase, plays indispensable roles in the podocyte. Autophagy 9:923-4|
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