Kidney Growth During Catabolic Illness: What It Does Not Destroy Makes It Grow Stronger

Chaperone-mediated autophagy (CMA). In CMA, cytoplasmic proteins with the KFERQ target sequence bind hsc73 and are unfolded. The complex binds to LAMP2a, and then the protein is transported through the lysosomal membrane. KFERQ, Lys-Phe-Glu-Arg-Gln; HSC 73, heat shock cognate protein of 73 kilodaltons; LAMP2a, lysosome-associated membrane protein 2a. Modified from Franch HA: Pathways of proteolysis affecting renal cell growth. Curr Opin Nephrol Hypertens 11:445–450, 2002.

Phosphatidyl-3 inositol kinase (PI 3 kinase) signaling in kidney cells. This cartoon shows growth factors (e.g., epidermal growth factor [EGF]) activating the p85 regulatory and p110 effector subunits of phosphatidyl 3 kinase (PI 3 kinase). The PI 3 kinase pathway stimulates protein synthesis through phosphoinositol dependent kinase (PDK1) and the mammalian target of rapamycin (mTOR) activating p70 S6 kinase (p70S6K). Akt blocks protein degradation in kidney cells by preventing the forkhead proteins (FoxO) from activating CMA. Note that in muscle cells, FoxO activates the proteasome by this same pathway. The PI 3 kinase pathway also has a weak effect to reduce proteasomal proteolysis through mTOR. Nutrient intake supports activation of mTOR while inhibiting FoxO activity by SIRT1. CMA, chaperone-mediated autophagy; Sirt1, Sirtulin-1; p110, phospinositide 3 kinase p110; p85, p85 subunits.