Effect of Mycophenolate Mofetil on Kallikrein Expression in the Kidney of 5/6 Nephrectomized Rats

Abstract

It has recently been proposed that tubulointerstitial damage plays a key role in the pathogenesis of sodium-dependent hypertension. Since components, enzymes and substrates, of the kallikrein-kinin system (KKS) are synthesized by connecting and collecting tubules, respectively, it is expected that damage of any origin, involving the tubulointerstitial compartment, may affect the functionality of these nephron segments and impair blood pressure control. Therefore, we analyzed renal kallikrein expression in the 5/6 renal ablation model, which is characterized by a progressive tubulointerstitial damage and systemic hypertension. In addition, we studied the renal expression of this enzyme after treatment of healthy and 5/6 nephrectomized rats with mycophenolate mofetil (MMF), an immunosuppressive drug known to reduce tubulointerstitial damage in this model. Twenty-six male Sprague-Dawley rats were included in this study. Seven 5/6 nephrectomized rats (Nx), 4 sham-operated (Sham) rats and 5 Nx rats treated with MMF (Nx + MMF) were studied 4 weeks after surgery. For comparison, 6 healthy rats treated with MMF at the same dose were compared with 4 vehicle-treated controls. Tubulointerstitial damage was significantly high in Nx compared with Nx-MMF and sham-operated rats. Blood pressure was significantly higher in Nx (178 ± 7.8 mm Hg) than in Sham (120 ± 2.0 mm Hg, p < 0.05) and Nx + MMF animals (154 ± 5.6 mm Hg, p < 0.05). Renal kallikrein expression, quantified by a computer image system was significantly lower in the Nx group (1,696 ± 437 density/mm²) than in Sham (9,779 ± 4,068 density/mm², p < 0.05), and in Nx + MMF groups (4,640 ± 1,578 density/mm², p < 0.05). Healthy animals treated with MMF did not show tubulointerstitial damage, changes in blood pressure nor changes in the expression of immunoreactive renal kallikrein suggesting that improvement in kallikrein expression after MMF treatment of 5/6 nephrectomy was not due to a direct effect of the drug on kallikrein-producing cells. Our results suggest that protection of the KKS after 5/6 nephrectomy may have additional renoprotective effects and may reduce the progression of renal disease.