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Role of Mammalian Target of Rapamycin Signaling in Compensatory Renal Hypertrophy

Jian-Kang Chen^*, Jianchun Chen^*, Eric G. Neilson^*, and Raymond C. Harris^*

Departments of ^* Medicine and Cell Biology, Vanderbilt University School of Medicine, and the Department of Veterans Affairs, Nashville, Tennessee

Address correspondence to: Dr. Jian-Kang Chen, Division of Nephrology, Departments of Medicine, Vanderbilt University School of Medicine, S 3223 Medical Center North, Nashville, TN 37232. Phone: 615-327-4751; Fax: 615-343-7156; jiankang.chen{at}vanderbilt.edu

Received for publication October 28, 2004. Accepted for publication February 13, 2005.

Loss of functioning nephrons stimulates the growth of residual kidney tissue to augment work capacity and maintain normal renal function. This growth largely occurs by hypertrophy rather than from hyperplasia of the remaining nephrons. The signaling mechanisms that increase RNA and protein synthesis during compensatory renal hypertrophy are unknown. This study found that the remaining kidney hypertrophied 42% by 16 d after unilateral nephrectomy (UNX) in DBA/2 mice. Immunoblotting analysis revealed increased phosphorylation of the 40S ribosomal protein S6 (rpS6) and the eukaryotic translation initiation factor (eIF) 4E-binding protein 1 (4E-BP1), the two downstream effectors of the mammalian target of rapamycin (mTOR). The highly specific mTOR inhibitor rapamycin blocked UNX-increased phosphorylation of both rpS6 and 4E-BP1. UNX increased the content of not only 40S and 60S ribosomal subunits but also 80S monosomes and polysomes in the remaining kidney. Administration of rapamycin decreased UNX-induced polysome formation and shifted the polysome profile in the direction of monosomes and ribosomal subunits. Pretreatment of the mice with rapamycin inhibited UNX-induced hypertrophy. These studies demonstrate that activation of the mTOR signaling pathway in the remaining kidney after UNX plays an essential role in modulating RNA and protein synthesis during development of compensatory renal hypertrophy.

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