Molecular mechanisms of tubulointerstitial hypertrophy and hyperplasia

Aside from the normal, sporadic turnover of epithelial cells along the adult nephron, most somatic cells in the kidney do not divide, or if they are obligated to respond to an external stimulus, there seems to be less hyperplasia in preference for cellular hypertrophy. A variety of pathophysiologic stimuli which provide temporary or permanent fixed reductions in renal function often result, for example, in compensatory enlargement of the kidney, principally in the tubulointerstitium [1]. Such adaptive responses are thought to provide a mechanism for redressing initial damage, as well as providing for a limited restoration of function. The renal hemodynamic alterations associated with these events, like increases in single nephron glomerular filtration rate (SNGFR) and glomerular blood flow, have been extensively reviewed elsewhere [2, 3], Changes in the size of the tubular nephron, as well as subsequent, late renal fibrosis have traditionally been considered a response to modifications in the mechanics of filtration—the so-called work hypothesis [4]. There is, however, alternative evidence in animals [5, 6], and humans [7], that the cellular processes of compensatory renal enlargement, themselves might share in the responsibility for the continued, long-term loss in remaining nephrons. Careful assessment of early enlargement parameters, like de novo synthesis of phosphatidylcholine, reveal for example, that some biochemical alterations occur earlier than the increase in SNGFR, or can be dissociated from semi-concurrent hemodynamic changes [8, 9]. Recent studies also provide evidence that growth factors can directly modulate renal hemodynamics, consistent with a contemporary view that initial compensatory responses might be responsible for subsequent alterations in hemodynamic parameters [10, 11]. The nature of the adaptive response of nephrons depends on the age of the individual, and whether the underlying initial insult is chronic or more acute. Tubular epithelial cells, for example, respond to acute tubular necrosis with proliferation and mitogenic activity, as defined by an increase in DNA synthesis. The renal growth response in neonatal animal following injury is also hyperplastic. Chronic damage of the adult kidney, in contrast, leans more towards compensatory renal hypertrophy with an increase in size and a rise in the protein/DNA ratio. In the 1960s, the view that approximately 75 to 80% of compensatory renal enlargement in adults was cellular hypertrophy, and the remaining 25 to 20% hyperplasia, is still widely held today [12]. While most anatomical parts of the nephron are probably involved in compensatory hypertrophy, the fact that a major constituent of kidney mass is proximal tubules suggests that an increase in size and protein content of proximal tubular cells may principally contribute to compensatory renal hypertrophy [13]. The present article, therefore, will examine some of these early-onset mechanisms of tubulointerstitial changes. Table 1 gives an overview of currently used experimental models of compensatory renal enlargement. Most models, particularly the ablative ones, result mainly in renal hypertrophy. Others, like the induction of acute tubular necrosis in animals by folate injection, however, are characterized by a mitogenic response producing hyperplasia [1, 14]. Despite the existence of a burgeoning literature dealing with more biochemical aspects of renal enlargement [14–16], the molecular mechanisms involved in the regulation of such changes are not formally understood. Especially incomplete is an understanding of the nuclear and cytoplasmic regulation of genes differentiating compensatory renal hypertrophy from true hyperplasia. Recent discoveries in the fields of epithelial growth factors, signal transduction and gene activation, however, have shed some new light on the molecular mechanisms of cellular enlargement. We will focus on these more recent findings.