Tacrolimus-induced hypertension and nephrotoxicity in Fawn-Hooded rats are attenuated by dual inhibition of renin–angiotensin system

Abstract

Chronic immunosuppressive therapy is often complicated by the development of both arterial hypertension and renal dysfunction. The principal aim of this study was to assess the effects of dual inhibition of renin-angiotensin system (RAS) and other antihypertensive treatment on blood pressure and renal function in normotensive and hypertensive Fawn-Hooded (FH) strains during chronic calcineurin inhibitor (CNI) administration. Combinations of perindopril (5 mg kg(-1) per day) and losartan (50 mg kg(-1) per day) or amlodipine (6 mg kg(-1) per day) and metoprolol (80 mg kg(-1) per day) were administered to normotensive (FHL) and hypertensive (FHH) rats, fed with diet containing tacrolimus (Tac; 12 mg kg(-1) per day). Tac-induced arterial hypertension in both animal strains (FHL: 151±4; FHH: 198±6 mm Hg) was prevented by dual RAS inhibition (FHL: 132±3 mm Hg, P<0.05; FHH: 153±3 mm Hg, P<0.05) as well as by a combination of amlodipine and metoprolol (FHL: 136±3 mm Hg, P<0.05; FHH: 166±4 mm Hg, P<0.05). However, significant nephroprotection was observed only in animals on dual RAS inhibition where albuminuria was reduced in both FHL (51.1±3.9 vs. 68.3±4.5 μg per day; P<0.05) and FHH rats (13.1±0.3 vs. 18.8±0.7 mg per day; P<0.05). We also found Tac-induced enhancement in renal angiotensin II activity that was significantly reduced by dual RAS inhibition in both FHL (63.5±3.2 vs. 23.1±3.0 fmol g(-1)) and FHH (79.8±8.5 vs. 32.2±5.8 fmol g(-1)). In addition, histological analysis revealed that RAS inhibition noticeably diminished glomerulosclerosis and tubulo-interstitial injury. This study indicates that dual blockade of RAS significantly attenuates Tac-induced arterial hypertension and nephrotoxicity in FH rats and further supports the notion that RAS inhibitors display efficient renoprotective properties during CNI treatment.

Evaluation of the Effect of Captopril and Losartan on Tacrolimus-induced Nephrotoxicity in Rats

“…According to the results, the long-term use of tacrolimus led to hypertension and renal damage in rats and chronic renal failure, especially due to increased renal RAS activity. Dual inhibition of RAS by ACEI and ARB drugs during four months of treatment with tacrolimus had antihypertensive and anti-nephrotoxic properties not only in rats with hypertension but also in samples with normal blood pressure [23]. In this respect, our findings are in accordance with the mentioned results, supporting the hypothesis that RAS inhibitors had proper protective properties against nephrotoxicity during treatment with a calcineurin inhibitor [24].…”

Effect of Empagliflozin on Tacrolimus-Induced Pancreas Islet Dysfunction and Renal Injury

“…This finding suggests that SGLT‐2 inhibition improves TAC‐induced glomerular injury, and this may be supported by a report that SGLT‐2 inhibition improves podocyte integrity in an experimental model of diabetic nephropathy . We further evaluated the intrarenal renin expression as a renoprotective mechanism of Em because renin–angiotensin system (RAS) activation is an important pathogenic mechanism in the development of TAC‐induced renal injury as well as diabetic nephropathy . In our study, we found that increased renin expression in the TAC group was significantly decreased with Em treatment, and this finding was consistent with a previous report that SGLT‐2 inhibitor improves diabetic nephropathy by suppressing renal RAS .…”

Pathophysiological Mechanisms of Calcineurin Inhibitor-Induced Nephrotoxicity and Arterial Hypertension

“…Some interesting data of the interaction between CNIs and RAS have been presented over recent years (Lee 1997, Mervaala et al 1999, Stilman et al 1995, Hošková et al 2014. The activation of RAS is initiated by direct induction of renin production and release in juxtaglomerular cells (Hoorn et al 2012).…”