Combination therapy with tranilast and angiotensin-converting enzyme inhibition provides additional renoprotection in the remnant kidney model

Abstract

Despite current therapy with agents that block the renin-angiotensin system, renal dysfunction continues to progress in a significant proportion of patients with kidney disease. Several pre-clinical studies have reported beneficial effects of tranilast, an inhibitor of transforming growth factor (TGF)-beta's actions in a range of diseases that are characterized by fibrosis. However, whether such therapy provides additional benefits in renal disease, when added to angiotensin-converting enzyme (ACE) inhibition, has not been explored. We randomized subtotally (5/6) nephrectomized rats to receive vehicle, the ACE inhibitor, perindopril (6 mg/l), tranilast (400 mg/kg/day), or their combination for 12 weeks. When compared with sham-nephrectomized animals, subtotally nephrectomized animals had reduced creatinine clearance, proteinuria, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and evidence of TGF-beta activity, as indicated by the abundant nuclear staining of phosphorylated Smad2. These manifestations of injury and TGF-beta activation were all attenuated by treatment with either tranilast or perindopril, with the latter also attenuating the animals' hypertension. When compared with single-agent treatment, the combination of tranilast and perindopril provided additional, incremental improvements in creatinine clearance, proteinuria, and glomerulosclerosis, and a reduction in nuclear phsopho-Smad2 beyond single-agent treatment. These findings indicate that the combination of tranilast and perindopril was superior to single-agent treatment on kidney structure and function in the remnant kidney model, and suggests the potential for such dual therapy in kidney disease that continues to progress despite blockade of the renin-angiotensin system.

Tranilast: A review of its therapeutic applications

“…In addition, macrophages were decreased by tranilast [159]. It reduced interstitial fibrosis, tubular atrophy, and albuminuria in rat models of UUO [160] and in a remnant kidney model [161]. In advanced experimental diabetic nephropathy, tranilast attenuated tubulointerstitial fibrosis and albuminuria [162].…”

Off the Beaten Renin–Angiotensin–Aldosterone System Pathway: New Perspectives on Antiproteinuric Therapy

“…In subnephrectomized rats, tranilast attenuated albuminuria, TGF-β activation, downstream Smad 2 phosphorylation, macrophage accumulation, glomerulosclerosis, and tubulointerstitial fibrosis. 70,71 In a model of IgA nephropathy, tranilast reduced mesangial cell proliferation, macrophage infiltration, glomerular type IV collagen deposition, and subsequently proteinuria. 72 …”

Renal protective effects of N-acetyl-Ser-Asp-Lys-Pro in deoxycorticosterone acetate–salt hypertensive mice

“…However, the mechanisms underlying development and progression of hypertensive renal injury are not fully understood. Several recent reports demonstrate that inflammation and fibrosis play an important role in high blood pressure-induced renal damage[1–4]. Moreover, proteinuria is a manifestation of hypertensive renal disease, and also accounts for increased cardiovascular risk in hypertensive patients[4,5].…”