Emerging evidence suggests that transforming growth factor-␤ (TGF-␤) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-␤ antibody (␣T) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-␤ system mediates the functional and structural changes of the more advanced stages of nephropathy, we tested whether chronic administration of ␣T prevents renal insufficiency and glomerulosclerosis in the db͞db mouse, a model of type 2 diabetes that develops overt nephropathy. Diabetic db͞db mice and nondiabetic db͞m littermates were treated intraperitoneally with ␣T or control IgG, 300 g three times per week for 8 wk. Treatment with ␣T, but not with IgG, significantly decreased the plasma TGF-␤1 concentration without decreasing the plasma glucose concentration. The IgG-treated db͞db mice developed albuminuria, renal insufficiency, and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding ␣1(IV) collagen and fibronectin. On the other hand, treatment with ␣T completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db͞db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factored for creatinine clearance was not significantly affected by ␣T treatment. We conclude that chronic inhibition of the biologic actions of TGF-␤ with a neutralizing monoclonal antibody in db͞db mice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.

Diabetic nephropathy is a well-known complication of diabetes and is a leading cause of chronic renal failure in the Western world. It is characterized by the accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments and by the thickening and hyalinization of intrarenal vasculature. The various cellular events and signaling pathways activated during diabetic nephropathy may be similar in different cell types. Such cellular events include excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products, activation of protein kinase C, increased expression of transforming growth factor β and GTP-binding proteins, and generation of reactive oxygen species. In addition to these metabolic and biochemical derangements, changes in the intraglomerular hemodynamics, modulated in part by local activation of the renin-angiotensin system, compound the hyperglycemia-induced injury. Events involving various intersecting pathways occur in most cell types of the kidney.

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Diabetic nephropathy is characterized by excessive amassing of extracellular matrix (ECM) with thickening of glomerular and tubular basement membranes and increased amount of mesangial matrix, which ultimately progress to glomerulosclerosis and tubulo-interstitial fibrosis. In view of this outcome, it would mean that all the kidney cellular elements, i.e., glomerular endothelia, mesangial cells, podocytes, and tubular epithelia, are targets of hyperglycemic injury. Conceivably, high glucose activates various pathways via similar mechanisms in different cell types of the kidney except for minor exceptions that are related to the selective expression of a given molecule in a particular renal compartment. To begin with, there is an obligatory excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products (AGEs), activation of protein kinase C (PKC), increased expression of transforming growth factor-beta (TGF-beta), GTP-binding proteins, and generation of reactive oxygen species (ROS). The ROS seem to be the common denominator in various pathways and are central to the pathogenesis of hyperglycemic injury. In addition, there are marked alterations in intraglomerular hemodynamics, i.e., hyperfiltration, and this along with metabolic derangements adversely compounds the hyperglycemia-induced injury. Here, the information compiled under various subtitles of this article is derived from an enormous amount of data summarized in several excellent literature reviews, and thus their further reading is suggested to gain in-depth knowledge of each of the subject matter.