Chronic Nicotine Accelerates Renal Injury and Cardiac Dysfunction Via Pressure Independent Actions of Endothelin and the Heme Oxygenase System

Background and Aim We examined potential mechanisms by which chronic nicotine (NIC) acts as a catalyst for renal, cardiac and vascular injury. Since, NIC enhances AngII‐induced increases in endothelin and blood pressure (BP), and decreases cyto‐protective HO responses, we tested the role of these in mediating the deleterious actions of NIC. Methods Sprague Dawley rats received nicotine (12μg/ml in their drinking water) with or without AngII (200ng/kg/min via SQ osmotic pump). Separate groups also received atrasentan (ATRA: 10mg/kg/day; a selective ET‐A antagonist) or hydralazine (HYD: 3 mg/kg/day). Blood pressure was measured by femoral artery catheter and the outer medullary reno‐vascular resistance (OM‐RVR) calculated. Renal function (plasma creatinine) was assessed by colorimetry and Urine endothelin‐1, pro‐inflammatory (TNF‐alfa), renal injury (NGAL and KIM‐1) and pro‐apoptotic (cyt‐c) markers assessed by ELISA. Heme oxygenase (HO) activity was evaluated based on the amount of bilirubin generated MAP (mm Hg) OM‐VR TPU/mm Hg Pl. Creat (mg/dl) TNFα (pg/μg) Endothelin‐1 (pg/mg creat) Cyt‐c (ng/μg protein) KIM‐1 (pg/μg protein) NGAL (UI/mg creat) HO Activity (nM of bilirubin/ml/hr) Control 85 ± 2 5 ± 0.3 0.3 ± 0.04 1.3 ± 0.2 0.03 ± 0.01 12 ± 1.2 57 ± 5 0.4 ± 0.05 0.4 ± 0.1 NIC 89 ± 2 5.3 ± 0.3 0.3 ± 0.02 1.2 ± 0.2 0.16 ± 0.02 * 23 ± 1.7* 52 ± 5 0.6 ± 0.1 1.3 ± 0.2* AngII 145 ± 1* 8.5 ± 0.3* 1.5 ± 0.07* 11 ± 1.8* 0.55 ± 0.04* 31 ± 2.3* 522 ± 50* 4.7 ± 0.5* 3.4 ± 0.3* AngII+ NIC 151 ± 1*# 12 ± 0.7*# 1.8 ± 0.03*# 18 ± 0.8*# 0.91 ± 0.06*# 84 ± 5.6*# 950 ± 60*# 9 ± 0.5*# 2.1 ± 0.2*# AngII+ 127 ± 4*#† 7.2 ± 0.2*#† 1.4 ± 0.05*#† 11 ± 1.3*† 0.03 ± 0.02#† 31 ± 4*† 550 ± 25*† 4 ± 0.6*† 2.8 ± 0.6* NIC+ATRA AngII+NIC+HYD 123 ± 4*#† 7.3 ± 0.5*#† 1.7 ± 0.05*#† 16 ± 0.9*#† 0.81 ± 0.03*#† 68 ± 2.3*#† 805 ± 22*#† 7 ± 0.4*#† 2.68 ± 0.4* P<0.05‐ * vs CT, # vs AngII, † vs. AngII+NIC MAP: Mean Arterial Pressure; OM‐VR: Outer medullary vascular resistance; Pl. Creat: Plasma Creatinine’ KIM‐1: Kidney Injury Molecule‐1; HO‐Activity: Heme‐oxygenase activity Results Atrasentan ameliorated NIC induced increase in cardiac BNP (from 0.63 ± 0.04 to 0.22 ± 0.02 ng/μg), cardiac TNF‐alfa (from 8.2 ± 0.2 to 4 ± 0.1 pg/μg), cardiac cytochrome c (from 23 ± 1 to 9 ± 0.3 ng/μg), without changing cardiac HO‐1 levels (1.4 ± 0.3 to 1.3 ± 0.4 ng/mg). Hence, atrasentan blunted the exacerbating effects of NIC on renal and cardiac parameters while decreasing BP, without altering the HO system. HYD, on the other hand, did not alter NIC induced exacerbation of renal dysfunction or changes in HO activity but only blunted the BP. Conclusion This suggests that the effects of NIC on the renal and cardiac dysfunction may be partially mediated through activation of the ET‐A receptor and is likely independent of BP and the HO‐pathway. Support or Funding Information This work was supported by NIH DK073401 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .