mTOR and rapamycin in the kidney

TY - JOUR

T1 - mTOR and rapamycin in the kidney

T2 - signaling and therapeutic implications beyond immunosuppression

AU - Huber, Tobias B

AU - Walz, Gerd

AU - Kuehn, E Wolfgang

PY - 2011/3

Y1 - 2011/3

N2 - The immunosuppressive drug rapamycin has helped to identify a large signaling network around the target of rapamycin (TOR) protein that integrates information on nutrient availability and growth factors to control protein synthesis and cell size. Studies using rapamycin in animal models of kidney disease indicate that mTOR deregulation has a role in glomerular disease, polycystic kidney disease, and renal cancer. The role of mTOR activation in podocytes is context dependent, and indirect evidence suggests that mTOR may have a role in chronic podocyte loss. Several lines of evidence show that cyst formation in polycystic kidney disease (PKD) involves mTOR activation and its upstream regulator TSC. Polycystin 1 regulates mTOR activity through different pathways, and TSC intersects with the primary cilium, a crucial cell organelle in the pathogenesis of PKD. Data from hamartoma syndromes provide clear evidence that mutation of members of the mTOR network results in renal cancers. The detailed analysis of renal cell carcinomas has revealed a positive feedback loop involving VHL and mTOR. Rapamycin and its derivatives have been approved for the treatment of advanced renal cancer and are being investigated for the treatment of PKD. Discrepancies exist between the effects of rapamycin in animal models and the clinical experience with patients, precluding the widespread use of mTOR inhibitors in kidney disease. The details of mTOR signaling in the kidney need to be clarified to hopefully develop targeted treatments for renal disease in the future.

AB - The immunosuppressive drug rapamycin has helped to identify a large signaling network around the target of rapamycin (TOR) protein that integrates information on nutrient availability and growth factors to control protein synthesis and cell size. Studies using rapamycin in animal models of kidney disease indicate that mTOR deregulation has a role in glomerular disease, polycystic kidney disease, and renal cancer. The role of mTOR activation in podocytes is context dependent, and indirect evidence suggests that mTOR may have a role in chronic podocyte loss. Several lines of evidence show that cyst formation in polycystic kidney disease (PKD) involves mTOR activation and its upstream regulator TSC. Polycystin 1 regulates mTOR activity through different pathways, and TSC intersects with the primary cilium, a crucial cell organelle in the pathogenesis of PKD. Data from hamartoma syndromes provide clear evidence that mutation of members of the mTOR network results in renal cancers. The detailed analysis of renal cell carcinomas has revealed a positive feedback loop involving VHL and mTOR. Rapamycin and its derivatives have been approved for the treatment of advanced renal cancer and are being investigated for the treatment of PKD. Discrepancies exist between the effects of rapamycin in animal models and the clinical experience with patients, precluding the widespread use of mTOR inhibitors in kidney disease. The details of mTOR signaling in the kidney need to be clarified to hopefully develop targeted treatments for renal disease in the future.

KW - Animals

KW - Autophagy

KW - Cilia

KW - Clinical Trials as Topic

KW - Diabetic Nephropathies

KW - Humans

KW - Immunosuppressive Agents

KW - Kidney Diseases

KW - Multiprotein Complexes

KW - Nephrons

KW - Podocytes

KW - Proteins

KW - Signal Transduction

KW - Sirolimus

KW - TOR Serine-Threonine Kinases

KW - TRPP Cation Channels

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Review

U2 - 10.1038/ki.2010.457

DO - 10.1038/ki.2010.457

M3 - SCORING: Review article

C2 - 21085109

VL - 79

SP - 502

EP - 511

JO - KIDNEY INT

JF - KIDNEY INT

SN - 0085-2538

IS - 5

ER -