#4544 the association of tamoxifen to the conservative ckd treatment promoted additional antifibrotic effects in a model of hypertensive nephrosclerosis

Abstract Background and Aims Chronic kidney disease (CKD) is an insidious, progressive and highly debilitating condition, which leads to the loss of renal function and to the need of life-sustaining renal replacement therapy. The conservative treatment of CKD is mainly based in the blockade of the renin-angiotensin-aldosterone system (RAAS), which can be associated to immunosuppressant drugs, according to the etiology of the renal injury. However, this pharmacological approach is not able to prevent CKD progression completely. Until the present moment, medical community still lack of a specific drug to effectively stop the progression of renal fibrosis associated to CKD, which once triggered became irreversible. Tamoxifen (TAM) is an estrogen receptor antagonist, widely employed for the clinical treatment of breast cancer, and responsible for saving a number of lives worldwide, in the past decades. This well-tolerated and cost-effective drug have been reported to exert antifibrotic effects in both experimental and human peritoneal fibrosis. Moreover, our research group already demonstrated that TAM efficiently prevented albuminuria, glomerulosclerosis, and interstitial fibrosis in a model of CKD. In the present study, we investigated if the association of TAM to the classic conservative treatment of CKD, here obtained by the association of Losartan (LOS) and Micofenolate Mofetil (MMF), could promote further renoprotection in an experimental model of hypertensive nephrosclerosis, induced by the chronic nitric oxide synthase blockade, obtained by the oral administration of L-NAME (NAME), associated to a high sodium (HS) diet, in rats. Method The experimental protocol was approved by the local Research Ethics Committee (CAPPesq) and was developed in strict conformity with the international standards for care and manipulation of laboratory animals. Thirty male Wistar rats were kept with a 3.2% HS diet for 15 days of adaptation, before the protocol start. After this period, the animals continued to receive the HS diet and were divided among 5 groups. CONT: receiving no further drugs or treatments, NAME: treated with 70 mg/kg/d of L-NAME, diluted in drinking water, LOS: NAME rats treated with 50mg/Kg/d of LOS, also diluted in drinking water, MMF: NAME rats treated with 10 mg/Kg/d of MMF given by gavage, TAM: NAME rats treated with 10 mg/Kg/d also by gavage, and LOS+MMF+TAM: NAME rats treated with all the drugs simultaneously. Systolic blood pressure (SBP), urinary albumin excretion (24 h uAE), glomerulosclerosis (GS), glomerular ischemia (GI), interstitial fibrosis (INT), tubulointerstitial infiltration of macrophages (CD68) and T-cells (CD3), as well as renal cortical interstitial collagen I (COLL1) and fibronectin (FIBRO) accumulation were evaluated after 30 days of treatment. Results The association of TAM to the classic treatment of CKD improved the renoprotection obtained by LOS+MMF. The triple combined treatment significantly reduced hypertension, albuminuria, glomerular structural damage, renal macrophage and T-cell infiltration in NAME rats, compared to the animals treated with the respective monotherapies. Moreover, both TAM alone or the association, were equally effective in reducing interstitial collagen and fibronectin accumulation, in NAME rats. Data are presented as Mean ± SE. For One-way ANOVA statistical analysis, we considered: p<0.05 vs.*CONT, #NAME, †LOS, §MMF, &TAM. Conclusion Our preliminary results shown TAM to be effective in reducing renal inflammation and fibrosis in the chronic nitric oxide synthase blockade model and to exert additional renoprotective effects when associated to LOS and MMF in all the analyzed parameters. Although further studies with different nephropathy models are still required in order to confirm our findings, here we suggest TAM to be a potential adjuvant in the conservative management of CKD.