Renal injury in diabetes mellitus is a major cause of morbidity and mortality. Approximately 30% of patients with type-I (insulin-dependent) diabetes mellitus (MOgensen 1982, 1990; BReyer 1992) and at least 10% of patients with type-II (non-insulin-dependent) diabetes mellitus (FABRE et al. 1982) will develop chronic renal failure requiring treatment in an end-stage renal disease program. Recent large-scale clinical trials have established that the best approach to the management of these patients is to detect the condition at an early stage and offer tight glycemic control (DCct Research Group 1993) and to treat hypertension preferably with angiotension-converting enzyme inhibitors (LEwis et al. 1993) in order to delay the progression of this life-threatening and costly complication of diabetes. The stages of progression of diabetic nephropathy are best understood in the setting of type-I diabetes mellitus, although recent studies in the Pima Indian community, where type-II diabetes mellitus affects a relatively large fraction of the population, have shown stages of progression of nephropathy similar to those seen in type-I patients (MYERS et al. 1991). Diabetic nephropathy encompasses a host of structural alterations which are characterized by early hypertrophy of both glomerular and tubuloepithelial elements, thickening of the glomerular and tubular basement membranes (GBM and TBM, respectively), and progressive accumulation of extracellular matrix components, principally in the glomerular mesangium (HOSTETTER 1986; ZIYADEH et al. 1989; FIORETTO et al. 1992; ZIYADEH 1993a). There is no question that the glomerular lesions are of fundamental importance for the expression of the functional derangements which characterize the stage of overt diabetic nephropathy, namely frank proteinuria, hypertension, and the progressive decline in glomerular filtration rate ( G F R ) (HOSTETTER 1986; ZIYADEH et al. 1989; FIORETTO et al. 1992). However, progressive tubulointerstitial fibrosis and renal arteriosclerosis, less widely recognized lesions, are also important components of diabetic nephropathy because they give rise to important alterations in tubular as well as glomerular function, and they often contribute singnificantly to the development of ischemic or obliterative, global glomerulosclerosis and thus to the marked reduction in G F R (GELLMAN et al. 1959; DECKERT et al. 1986; ZIYADEH and GOLDFARB 1991; LANE et al. 1993). In fact, the degree of tubulointerstitial fibrosis in diabetic nephropathy closely correlates with the magnitude of mesangial matrix expansion (MAUER et al. 1984) and with the decline in G F R (BADER et al. 1980). Thus, as with many different renal glomerular diseases, the severity of the accompanying tubular atrophy and interstitial fibrosis is an excellent predictor of impaired kidney function, measured principally as a reduction in G F R (BOHLE et al. 1977a,b,c). Therefore, a full understanding of the mechanisms that culminate in irreversible kidney failure in diabetes mellitus requires a closer look at the status of the tubulointerstitium in this disease. Another characteristic abnormality of the tubuloepithelial and interstitial compartments in the diabetic state in nephromegaly (SEYER-HANSEN 1983; RASCH 1984; KLEINMAN a n d FINE 1988; FLYVBJERG et al. 1992; ZIYADEH 1993). Nephromegaly is an early feature of the involvement of the kidney in this disease and is predominantly reflective of increased renal ubule mass, mostly as a consequence of cellular ypertrophy of the tubuloepithelium (SEYER-HANSEN et al. 1980; RASCH 1984). Much of the controversy in the literature on the pathogenesis of renal hypertrophy in type-I diabetes relates to whether an increase in GFR is a casual factor in the enesis of hypertrophy, or whether it is secondary to a primary increase in glomerular and kidney size (SCHWIEGER and FINE 1990). The importance of renal hypertrophy in the development of abnormalities in kidney function remains unsettled, but it can be speculated that tubular hypertrophy may contribute to the features of the disease, in a manner somewhat analogous to the more established relationship between glomerular hypertrophy and the eventual development of glomerulosclerosis (FOGO and ICHIKAWA 1989).