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Pleiotropic effects of amitriptyline ameliorate renal fibrosis

2009; Elsevier BV; Volume: 75; Issue: 6 Linguagem: Inglês

10.1038/ki.2008.655

1523-1755

Jeremiah J. Morrissey,

Kidney Stones and Urolithiasis Treatments

Unilateral ureteral obstruction is a well-established model of renal fibrosis used by many investigators to test various compounds for their ability to ameliorate kidney disease. Achar et al. treated ureterally obstructed mice with the tricyclic antidepressant amitriptyline and found that this inhibited inflammation, myofibroblast formation, and several other indices of renal fibrosis. This pleiotropic antidepressant agent appears to have antifibrotic effects in the kidney and other organ systems. Unilateral ureteral obstruction is a well-established model of renal fibrosis used by many investigators to test various compounds for their ability to ameliorate kidney disease. Achar et al. treated ureterally obstructed mice with the tricyclic antidepressant amitriptyline and found that this inhibited inflammation, myofibroblast formation, and several other indices of renal fibrosis. This pleiotropic antidepressant agent appears to have antifibrotic effects in the kidney and other organ systems. On the basis of their previous work, using amitriptyline to relax smooth muscle,1.Achar E. Achar R.A. Paiva T.B. et al.Amitriptyline eliminates calculi through urinary tract smooth muscle relaxation.Kidney Int. 2003; 64: 1356-1364Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Achar et al.2.Achar E. Maciel T.T. Collares C.F. et al.Amitriptyline attenuates interstitial inflammation and ameliorates the progression of renal fibrosis.Kidney Int. 2009; 75: 596-604Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar (this issue) treated mice with unilateral ureteral obstruction (UUO) with this multifaceted antidepressant and found that it inhibited the progression of renal fibrosis. In particular, there was a significant reduction in the infiltration of the interstitium by CD68-positive macrophages, a result equivalent to that of pretreatment of the mice with mycophenolate mofetil or whole-body X-irradiation prior to the obstruction. In addition, there were significant reductions in the expression of α-smooth muscle actin, osteopontin, transforming growth factor-β, monocyte chemotactic protein-1, and intercellular adhesion molecule-1 due to antidepressant treatment. The decreased expression of these indices of kidney fibrosis was equivalent or superior to their reductions by either immune-suppressor pretreatment. The question here is: how does an antidepressant accomplish this off-label reduction in kidney fibrosis? The authors pose several mechanistic possibilities (Figure 1) each of which could contribute, individually and/or in synergy, to the reduction in renal fibrosis. The tricyclic compounds have analgesic effects, independent of their antidepressant properties, on chronic pain associated with rheumatologic conditions, postherpetic neuralgia, or diabetic neuropathy even in low amounts such that the 1 mg/kg/d oral dose used by Achar et al.2.Achar E. Maciel T.T. Collares C.F. et al.Amitriptyline attenuates interstitial inflammation and ameliorates the progression of renal fibrosis.Kidney Int. 2009; 75: 596-604Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar to block renal fibrosis is not an excessive dose. One area, not developed by the authors, where amitriptyline treatment could have an impact on kidney fibrosis is related to ceramide metabolism and its role as a stress-response molecule in cell apoptosis and inflammation. First, however, the utility of the UUO model in the study of renal fibrosis needs to be established. This model is gaining in popularity such that at the 2008 annual meeting of the American Society of Nephrology, almost 60 abstracts, nine of which were selected for oral presentation, used this model to study mechanisms of and the possible treatment of kidney fibrosis. Inflammation of the kidney tubulointerstitium results in fibrosis, which is a major factor in the progressive loss of renal function in patients with a wide variety of kidney diseases. Over two-thirds of the kidney volume is composed of tubular epithelial cells, with the remainder residing in the glomerular and the interstitial spaces. Most of the interstitial cells are associated with the rich vascular network of the kidney along with a small number of tenant mononuclear cells and fibroblasts. UUO is a model of renal fibrosis, encompassing many aspects of other forms of kidney disease, such as those caused by streptozotocin, cyclosporin, aminonucleoside, adriamycin, angiotensin II, and ischemia–reperfusion. This is a highly reproducible model applicable to fetal, neonatal, and adult animals that features infiltration of the kidney by monocytes and macrophages, fibroblast differentiation and proliferation, and increased extracellular matrix protein deposition. In an attempt to maintain the integrity of tubules, there is activation of proliferative pathways within the epithelial cells to repopulate themselves. If the proliferative forces or homeostatic factors within the kidney dissipate, apoptosis overwhelms the ability of tubular epithelial cells to survive, and tubular atrophy ensues, thus furthering the loss of kidney function. This UUO model has been used to test the contribution of epithelial–mesenchymal transdifferentiation to the formation of myofibroblasts positive for α-smooth muscle actin or fibroblast-specific protein-1 (FSP-1, or S100A4) within the interstitium. Features associated with the progression of renal fibrosis occur in an accelerated time frame, allowing investigators to use this model to gain valuable information on pathophysiologic mechanisms of the initiation and progression of renal fibrosis. These mechanisms and the contributions of angiotensin II, transforming growth factor-β, and tumor necrosis factor-α to kidney fibrosis have been extensively reviewed by Klahr and Morrissey3.Klahr S. Morrissey J. Obstructive nephropathy and renal fibrosis.Am J Physiol Renal Physiol. 2002; 283: F861-F875Crossref PubMed Scopus (460) Google Scholar and more recently by Misseri and Meldrum,4.Misseri R. Meldrum K.K. Mediators of fibrosis and apoptosis in obstructive uropathies.Curr Urol Rep. 2005; 6: 140-145Crossref PubMed Scopus (37) Google Scholar Bascands and Schanstra,5.Bascands J.-L. Schanstra J.P. Obstructive nephropathy: insights from genetically engineered animals.Kidney Int. 2005; 68: 925-937Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar and Chevalier.6.Chevalier R.L. Obstructive nephropathy: towards biomarker discovery and gene therapy.Nat Clin Pract Nephrol. 2006; 2: 157-168Crossref PubMed Scopus (147) Google Scholar Because this is a unilateral disease model, there is no overt hypertension or uremia to complicate the interpretation of results. Operational assessment of the formerly obstructed kidney can be made following relief of the obstruction by measurement of individual kidney function3.Klahr S. Morrissey J. Obstructive nephropathy and renal fibrosis.Am J Physiol Renal Physiol. 2002; 283: F861-F875Crossref PubMed Scopus (460) Google Scholar, 7.Cochrane A.L. Kett M.M. Samuel S.C. et al.Renal structural and functional repair in a mouse model of reversal of ureteral obstruction.J Am Soc Nephrol. 2005; 16: 3623-3630Crossref PubMed Scopus (122) Google Scholar or by reimplantation of the obstructed ureter and nephrectomy of the contralateral kidney to serially measure kidney function in the same test animals.8.Tapmeier T.T. Brown K.L. Tang Z. et al.Reimplantation of the ureter after unilateral ureteral obstruction provides a model that allows functional evaluation.Kidney Int. 2008; 73: 885-889Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Overall, UUO is a useful model of kidney injury and can be used to test therapeutic strategies for reversing renal fibrosis and preserving or restoring renal function. Amitriptyline and other tricyclic antidepressants fit into this discussion by virtue of their ability to cause degradation of acid sphingomyelinase,9.Hurwitz R. Ferlinz K. Sandhoff K. The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts.Biol Chem Hoppe Seyler. 1994; 375: 447-450Crossref PubMed Scopus (205) Google Scholar an enzyme contributing to ceramide formation that is best known for its involvement in the lysosomal-storage disorder Niemann–Pick disease. Modulation of ceramide levels by tricyclic antidepressants has been used to decrease lung injury in experimental cystic fibrosis10.Teichgraber V. Ulrich M. Endlich N. et al.Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis.Nat Med. 2008; 14: 382-391Crossref PubMed Scopus (419) Google Scholar and liver cirrhosis,11.Lang P.A. Schenck M. Nicolay J.P. et al.Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.Nat Med. 2007; 13: 164-170Crossref PubMed Scopus (375) Google Scholar but at higher doses than Achar et al.2.Achar E. Maciel T.T. Collares C.F. et al.Amitriptyline attenuates interstitial inflammation and ameliorates the progression of renal fibrosis.Kidney Int. 2009; 75: 596-604Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar used. Mice deficient in acid sphingomyelinase were found to be resistant to cisplatin-induced gastrointestinal damage,12.Rebillard A. Rioux-Leclercq N. Muller C. et al.Acid sphingomyelinase deficiency protects from cisplatin-induced gastrointestinal damage.Oncogene. 2008; 27: 6590-6595Crossref PubMed Scopus (30) Google Scholar and hepatocytes from such mice had decreased copper-induced apoptosis.11.Lang P.A. Schenck M. Nicolay J.P. et al.Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.Nat Med. 2007; 13: 164-170Crossref PubMed Scopus (375) Google Scholar Thus, extrapolating from these studies, a beneficial effect of amitriptyline in the UUO study of Achar et al.2.Achar E. Maciel T.T. Collares C.F. et al.Amitriptyline attenuates interstitial inflammation and ameliorates the progression of renal fibrosis.Kidney Int. 2009; 75: 596-604Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar could be an inhibition of acid sphingomyelinase that, in turn, inhibits tubular-cell apoptosis and interstitial inflammation. This coupled with effects of amitriptyline on cytokine release, cited by the authors, could account for the renoprotective effects of the antidepressant in the UUO model. A significant diminution in the measured indices of renal fibrosis apparently occurred between 3 and 5 days of ureteric obstruction when the amitriptyline was given at the time of the obstruction. It would be interesting to give the antidepressant at different times after initiating renal fibrosis to see whether this is a true viable treatment option and not just a preventive measure. Studies using mice in which the acid sphingomyelinase gene has been knocked out would help to show whether the protective effect of amitriptyline is indeed dependent on this enzyme or whether there are additional pleiotropic effects involving other metabolic pathways. The issue of redundant functional genes masking changes in gene activity in gene knockout mice in the UUO model has been addressed previously.3.Klahr S. Morrissey J. Obstructive nephropathy and renal fibrosis.Am J Physiol Renal Physiol. 2002; 283: F861-F875Crossref PubMed Scopus (460) Google Scholar, 5.Bascands J.-L. Schanstra J.P. Obstructive nephropathy: insights from genetically engineered animals.Kidney Int. 2005; 68: 925-937Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar On the basis of this study and their long-standing use for mood alteration, Achar et al.2.Achar E. Maciel T.T. Collares C.F. et al.Amitriptyline attenuates interstitial inflammation and ameliorates the progression of renal fibrosis.Kidney Int. 2009; 75: 596-604Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar suggest that the tricyclic antidepressants may be used as future therapies to inhibit the progression of renal disease. This class of drugs, however, is not without unintended consequences, so patient monitoring is essential. These side effects (Toxnet.nlm.nih.gov) include, but are not limited to, dry mouth, orthostatic hypotension, and tachycardia. It may turn out, however, that an unintended consequence of the tricyclic antidepressants is a viable treatment delaying or reversing the progression of renal fibrosis, thus maintaining or restoring kidney function.