p 27 Kip 1 : The “ Rosebud ” of Diabetic Nephropathy ?

“Rosebud” was the last enigmatic word of dying protagonist Charles Foster Kane in Orson Welles’ 1941 masterpiece Citizen Kane, considered by many cineastes as the best movie ever made. The search for its meaning is the film’s theme. The investigative reporter thinks that by discovering what or who “rosebud” was will possibly provide a simple secret to Kane’s mysterious, complex life. We are facing an anticipated epidemic of ends-tage renal disease in the next decade, which will largely be due to diabetic nephropathy. This reflects our inability to prevent and control the disease; therefore, anything that has promise to contribute to controlling diabetic nephropathy is a cause for considerable excitement. What is p27, and is it the missing link in understanding the pathogenesis and potential treatment of diabetic nephropathy? This question is posed by Awazu et al. in this issue of JASN. In attempting to answer this question, we must first understand the complicated mechanisms of cell cycle regulation, which have been a major focus of many laboratories over the past two decades, culminating in awarding the Nobel prize for medicine in 2001 to Hartwell and Hunt. Depending on the cell type and underlying specific cell injury (1), renal cells respond by undergoing proliferation, apoptosis, de-differentiation, or hypertrophy (2,3). Morphometric studies on renal specimens from patients with type 1 and 2 diabetes show characteristic glomerular hypertrophy, particularly of mesangial cells, but also of endothelial cells, early in diabetic nephropathy (1,4,5). Hypertrophy is biochemically defined as an increase in protein and RNA content, but without DNA replication (6). Morphometrically, this is accompanied by an increase in cell size. A more detailed analysis of the evolution of diabetic nephropathy that can only be performed in animal models shows a biphasic mesangial growth response, with early proliferation and subsequent hypertrophy (7). These growth responses to the diabetic environment are ultimately governed at the level of the nucleus (5), providing a rationale for the study of cell cycle regulatory proteins in diabetic nephropathy, as was undertaken by Awazu et al. in this issue of JASN (8). It has been known for more than a century that the growth of a cell has two main phases: interphase and mitosis. Figure 1 shows that interphase is further divided into G1, S, and G2 phases (9). Nondividing cells enter the G1 phase from a quiescent G0 phase, pass through G1 into the S phase, where DNA replication takes place, and enter mitosis after progressing through G2. Once in G1, a cell can undergo three fates. First, the classic proliferation pathway requires that cells progress from G1, though S and M phases, followed by cytokinesis (cell division) (Figure 1). Second, upon G1 entry, cells can exit G1 or any phase of the cell cycle to undergo apoptosis. Third, and the focus of this editorial, is that after G1 entry, there is arrest at the G1/S transition, which prevents DNA synthesis. However, under these circumstances, because the protein content increases in G1 phase (in anticipation of the cell dividing into two daughter cells), a block at G1/S phase prevents DNA synthesis, resulting an increase in the protein:DNA ratio, which causes an increase in cell size (hypertrophy) (Figure 1).