Mycophenolate mofetil slows progression in anti-thy1-induced chronic renal fibrosis but is not additive to a high dose of enalapril

Abstract

Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg·kg body wt−1·day−1), cGS plus high-dose enalapril (12 mg·kg body wt−1·day−1), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-β1, fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high-dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease.

Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat

“…Chronic-progressive glomerulosclerosis (cGS) was produced by surgically removing one kidney and intravenously injecting the monoclonal antibody mAb 1-22-3 (5 mg/kg body wt in PBS, pH ϭ 7.4) 3 days later (17,21,27). The mAb 1-22-3 antibody binds to a thy1-like antigen on the surface of mesangial cells of the kidney and causes a fast complement-dependent and NO-dependent mesangial cell lysis within the next 24 h (17,27). The progression in cGS is linked to the uninephrectomy that is performed before anti-thy1 antibody injection, since the glomerular disease resolves over ϳ4 wk in animals with two kidneys (17,21,27).…”

“…The mAb 1-22-3 antibody binds to a thy1-like antigen on the surface of mesangial cells of the kidney and causes a fast complement-dependent and NO-dependent mesangial cell lysis within the next 24 h (17,27). The progression in cGS is linked to the uninephrectomy that is performed before anti-thy1 antibody injection, since the glomerular disease resolves over ϳ4 wk in animals with two kidneys (17,21,27). Control animals were injected with equal volumes of PBS only.…”

“…When acute mesangioproliferative glomerulonephritis advances, the histological picture is characterized by glomerulosclerosis and fibrotic destruction of the corresponding nephron tubule (tubulointerstitial atrophy and fibrosis). The latter closely parallels the ongoing loss in renal function (13,14,17). Progression in mesangioproliferative glomerulonephritis generally involves increasing proteinuria, pathological renal extracellular matrix protein accumulation, cell proliferation, and inflammatory cell infiltration (3,15,17,23,28).…”

“…Progression in mesangioproliferative glomerulonephritis generally involves increasing proteinuria, pathological renal extracellular matrix protein accumulation, cell proliferation, and inflammatory cell infiltration (3,15,17,23,28). Pharmacological treatment of progressive mesangioproliferative disease is practically limited to RAS inhibition using angiotensin-converting enzyme inhibitors or AT 1 receptor antagonists, which serves to decelerate but generally not halt the advance of the disease (13,17,28).…”

“…In this model, a single injection of a high dose of anti-thy1 antibody into uninephrectomized rats leads to a short-term complement-and nitric oxide-mediated acute glomerulonephritis, which then, over months, progresses autonomously toward persistent glomerulosclerosis, marked tubulointerstitial fibrosis, and renal insufficiency in a not primarily immune-mediated manner (17,21,27). This model has been termed anti-thy1-induced chronic glomerulosclerosis or anti-thy1-induced renal fibrosis (17,27). The course of experimental progressive anti-thy1-induced chronic glomerulosclerosis mimics to a relevant degree advancing mesangioproliferative nephropathy in humans and thus can act as an experimental model for studying human disease.…”