Add-On Anti–TGF-β Antibody to ACE Inhibitor Arrests Progressive Diabetic Nephropathy in the Rat

Abstract

Abstract. Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth factor-␤ (TGF-␤) in the pathogenesis of diabetic kidney disease, this study tested the effect of simultaneously interrupting TGF-␤ and angiotensin II on disease progression in diabetic rats with overt nephropathy. Diabetes was induced by streptozotocin injection in uninephrectomized rats. Diabetic rats received murine (1D11) or human anti-TGF-␤ monoclonal antibodies alone or in combination with lisinopril, 13C4 irrelevant murine antibody, saline or lisinopril from month 4 (when animals had proteinuria) to month 8. Normal animals served as controls. Systolic BP increase was controlled by single treatments and even more by the combined therapies. 1D11 and lisinopril kept proteinuria at levels numerically lower than irrelevant antibody and saline, while CAT-192 was ineffective. The addition of either TGF-␤ antibody to lisinopril normalized proteinuria. Consistent results were obtained for glomerulosclerosis and tubular damage, which were abrogated by the combined therapy. Interstitial volume expansion and infiltration of lymphocytes/macrophages were limited by 1D11 and lisinopril and further reduced by their combination. The increase of type III collagen in the renal interstitium was partially attenuated by 1D11 and lisinopril while normalized by their combination. It is concluded that anti-TGF-␤ antibody when added to a background of chronic angiotensin-converting enzyme (ACE) inhibition fully arrests proteinuria and renal injury of overt diabetic nephropathy, providing a novel route to therapy and remission of disease for diabetic patients who do not respond to RAS inhibition. Diabetic nephropathy, a major long-term complication of diabetes mellitus, is the most common cause of end-stage renal disease requiring dialysis worldwide (1,2) and is becoming a staggering challenge to public healthcare systems due to the prohibitive costs of renal replacement therapy that could become unaffordable even for developed countries. Typical histologic features characterize diabetic nephropathy, including expansion of the extracellular matrix in the glomerular mesangium, thickening of glomerular and tubular membranes, and tubulointerstitial fibrosis, all of them contributing to the inexorable progressive deterioration of renal function (3).Among treatment options for diabetes, agents that inhibit the renin-angiotensin system (RAS) are particularly effective in reducing renal disease progression (4). This is not simply a function of the effect on systemic and glomerular hypertension, but it can be attributed to the unique property of this class of drugs of limiting excess protein ultrafiltration and its deleterious consequences (5). Angiotensin-converting enzyme inhibitor (ACEi) effectiveness, however, depends on timing of treatment. Experimental data in rats with streptozotocin-induced diabete...

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

“…Other direct anti-TGF-␤ antagonists used in rodent diabetic models, primarily neutralizing antibodies such as 1D11 and CAT-192, reduce proteinuria and/or glomerulosclerosis. 14 In one study, the ID11 antibody reduced mesangial sclerosis, although proteinuria was not significantly improved. 12 The timing of anti-TGF-␤ administration also affects outcomes in streptozotocin-treated rats with early treatment (27 to 52 weeks) but not late treatment (52 to 61 weeks), having significant beneficial effects on glomerulosclerosis and proteinuria.…”

Effect of combination therapy with enalapril and the TGF-β antagonist 1D11 in unilateral ureteral obstruction

“…It has been used as a single agent in several models of renal disease including UUO, diabetes, glomerulonephritis, and cyclosporine nephropathy (2,18,20,36). Similarly, either ACE inhibitors or ANG II antagonists have been used both clinically and experimentally in both renal and cardiac disease models (13,16,17,25,30).…”

“…Similarly, either ACE inhibitors or ANG II antagonists have been used both clinically and experimentally in both renal and cardiac disease models (13,16,17,25,30). It was shown that the combination of both 1D11 and an ACE inhibitor provided superior protection in either experimental diabetes or glomerulonephritis, than either drug alone (2,36). In the present study, we sought to determine whether a combination of 1D11 and the ACE inhibitor, enalapril, would provide more protection against renal damage in UUO than each drug used separately.…”

“…In a model of diabetic nephropathy, it was shown that the combination of 1D11 and lisinopril (ACE inhibitor) fully arrested both proteinuria and renal injury, whereas neither treatment by itself was totally effective (2). Likewise, in a model of glomerulonephritis, combination of enalapril and 1D11 had an enhanced antifibrotic effect, compared with the two drugs given separately (36).…”

Glomerulonephritis, Pathogenetic Mechanisms and Therapeutic Options: An Overview

“…These drugs have proven useful in experimental rapidly progressive GN, where they inhibited the formation of crescents [61][62][63][64][65][66][67], and in mouse strains having developed spontaneously SLE [68].…”