Molecular mechanisms of diabetic renal hypertrophy Gunter Wolf, Fuad N. Ziyadeh  Kidney International  Volume 56, Issue 2, Pages 393-405 (August 1999) DOI: 10.1046/j.1523-1755.1999.00590.x Copyright © 1999 International Society of Nephrology Terms and Conditions

Figure 1 Overview of cell cycle regulation. In order to proliferate, cells must enter the cell cycle from a quiescent G0 phase, progress through all the remaining phases (G1, S, G2), and successfully complete mitosis (left side of the figure). In contrast, cells undergoing cellular hypertrophy, for example, in diabetic nephropathy, actively enter the cell cycle but do not progress beyond the late G1 phase. Heterodimeric complexes of cyclin E-CdK2, and cyclins D1-D3-CdK4,6 have kinase activities and drive cells through G1 into the S phase by phosphorylating target proteins, including the protein product of the retinoblastoma gene (top of right side of figure). CdK-inhibitors such as p27Kip1 or p21 bind to cyclin-CdK complexes and inhibit their kinase activity (bottom of right side of figure). Increased expression of p27Kip1 protein by hyperglycemia arrests cells in the late G1 phase of the cell cycle and therefore facilitates cellular hypertrophy as well as protect against apoptosis. Kidney International 1999 56, 393-405DOI: (10.1046/j.1523-1755.1999.00590.x) Copyright © 1999 International Society of Nephrology Terms and Conditions

Figure 2 Pivotal role of the CdK-inhibitor p27Kip1 in diabetes-induced hypertrophy of renal cells. High glucose, through activation of protein kinase C (PKC), as well as induction of TGF-βbgr;, leads to stimulation of expression of p27Kip1 protein. Additional factors such as angiotensin II (Ang II), and perhaps hemodynamic stretch and glycated proteins such as advanced glycation end products (AGE) may further stimulate p27Kip1 expression. When the total amount of p27Kip1 protein is increased, there is increased binding to cyclin-CdK complexes, inhibition of their activity, and cell cycle arrest in the G1 phase, with subsequent development of cellular hypertrophy. Additional CdK-inhibitors such as p21 may also contribute to this G1-exit block. It remains unclear whether or not the G1-phase arrest is a prerequisite for matrix accumulation, a classic hallmark of diabetic nephropathy. Kidney International 1999 56, 393-405DOI: (10.1046/j.1523-1755.1999.00590.x) Copyright © 1999 International Society of Nephrology Terms and Conditions