Renal Heme Oxygenase-1 Induction with Hemin Augments Renal Hemodynamics, Renal Autoregulation, and Excretory Function

Heme oxygenases (HO-1; HO-2) catalyze conversion of heme to free iron, carbon monoxide, and biliverdin/bilirubin. To determine the effects of renal HO-1 induction on blood pressure and renal function, normal control rats (n=7) and hemin-treated rats (n=6) were studied. Renal clearance studies were performed on anesthetized rats to assess renal function; renal blood flow (RBF) was measured using a transonic flow probe placed around the left renal artery. Hemin treatment significantly induced renal HO-1. Mean arterial pressure and heart rate were not different (115±5 mmHg versus 112±4 mmHg and 331±16 versus 346±10 bpm). However, RBF was significantly higher (9.1±0.8 versus 7.0±0.5 mL/min/g, P<0.05), and renal vascular resistance was significantly lower (13.0±0.9 versus 16.6±1.4 [mmHg/(mL/min/g)], P<0.05). Likewise, glomerular filtration rate was significantly elevated (1.4±0.2 versus 1.0±0.1 mL/min/g, P<0.05), and urine flow and sodium excretion were also higher (18.9±3.9 versus 8.2±1.0 μL/min/g, P<0.05 and 1.9±0.6 versus 0.2±0.1 μmol/min/g, P<0.05, resp.). The plateau of the autoregulation relationship was elevated, and renal vascular responses to acute angiotensin II infusion were attenuated in hemin-treated rats reflecting the vasodilatory effect of HO-1 induction. We conclude that renal HO-1 induction augments renal function which may contribute to the antihypertensive effects of HO-1 induction observed in hypertension models

Tadalafil for the Treatment of Pulmonary Arterial Hypertension A Double-Blind 52-Week Uncontrolled Extension Study

ObjectivesThe aim of this study was to evaluate the long-term safety and durability of efficacy of tadalafil for pulmonary arterial hypertension.BackgroundTadalafil is an oral phosphodiesterase-5 inhibitor approved for PAH treatment. In the multicenter, placebo-controlled, randomized, 16-week PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study, tadalafil 40 mg improved exercise capacity and delayed clinical worsening.MethodsEligible patients from PHIRST received once-daily tadalafil 20 mg (T20 mg) or 40 mg (T40 mg) (n = 357) in the double-blind, 52-week, uncontrolled extension study (PHIRST-2); 293 patients completed PHIRST-2. Durability of efficacy was explored using the 6-min walk distance (6MWD) test. Clinical worsening and changes in World Health Organization functional class were evaluated.ResultsThe safety profile of tadalafil in PHIRST-2 was similar to that in PHIRST, with typical phosphodiesterase-5 inhibitor adverse events. The 6MWDs achieved in PHIRST for the subset of patients receiving T20 mg and T40 mg in both PHIRST and PHIRST-2 (406 ± 67 m [n = 52] and 413 ± 81 m [n = 59] at PHIRST-2 enrollment, respectively) were maintained at PHIRST-2 completion (415 ± 80 m [n = 51] and 410 ± 78 m [n = 59], respectively). Numerically fewer patients who were on T40 mg in PHIRST and PHIRST-2 experienced World Health Organization functional class deterioration (6% [n = 5]) compared with those randomized to T20 mg (9% [n = 7]) across both studies. Post hoc analyses showed that background bosentan use and higher 6MWD at PHIRST baseline were associated with fewer clinical worsening events.ConclusionsLong-term treatment with tadalafil was well tolerated in patients with pulmonary arterial hypertension. In patients receiving either T20 mg or T40 mg, the improvements in 6MWD demonstrated in the 16-week PHIRST study appeared sustained for up to 52 additional weeks of treatment in PHIRST-2. (Pulmonary Arterial Hypertension and Response to Tadalafil Study; NCT00549302

Increase in heme oxygenase-1 levels ameliorates renovascular hypertension

Increase in heme oxygenase-1 levels ameliorates renovascular hypertensionBackgroundThe heme oxygenase system (HO-1 and HO-2) catalyzes the conversion of heme to free iron, carbon monoxide (CO), a vasodepressor, and biliverdin, which is further converted to bilirubin, an antioxidant. HO-1 induction has been shown to suppress arachidonic acid metabolism by cytochrome P450 (CYP450) monooxygenases and cyclooxygenases (COX), and to decrease blood pressure in spontaneously hypertensive rats (SHR). The Goldblatt 2K1C model is a model of renovascular hypertension in which there is increased expression of COX-2 in the macula densa and increased renin release from the juxtaglomerular apparatus of the clipped kidney. We examined whether HO-1 overexpression, as a prophylactic approach, would attenuate renovascular hypertension and evaluated potential mechanisms that may account for its effect.Methods2K1C rats were treated with cobalt protoporphyrin (CoPP) or tin mesoporphyrin (SnMP) one day before surgery and weekly for three weeks thereafter. We measured systolic blood pressure, HO activity, HO-1, HO-2, COX-1 and COX-2 protein expression, heme content, and nitrotyrosine levels as indices of oxidative stress. Urinary prostaglandin excretion (PGE2), plasma renin activity (PRA), and plasma aldosterone levels were also measured.ResultsCoPP administration induced renal HO-1 expression by 20-fold and HO activity by 6-fold. This was associated with a reduction in heme content, nitrotyrosine levels, COX-2 expression and urinary PGE2 excretion, and attenuation of the development of hypertension in the 2K1C rats. There was no decrease in plasma renin activity; however, plasma aldosterone levels were significantly lower. In the 2K1C SnMP-treated rats, blood pressure was significantly higher than that of untreated 2K1C rats throughout the study, and the difference in the size of the smaller left clipped kidney compared to the nonclipped right kidney was significantly increased.ConclusionThese findings define an action of prolonged HO-1 induction to interrupt and counteract the influence of the renin-angiotensin-aldosterone system (RAAS) to increase in blood pressure in the 2K1C model of renovascular hypertension. Multiple mechanisms include a decrease in oxidative stress as indicated by the decrease in cellular heme and nitrotyrosine levels, an anti-inflammatory action as evidenced by a decrease in COX-2 and PGE2, interference with the action of angiontensin II (Ang II) as evidenced by an increase in PRA in the face of a decrease in PGE2 and aldosterone, as well as the inhibition of aldosterone synthesis

Heme oxygenase induction attenuates afferent arteriolar autoregulatory responses

Heme oxygenases (HO-1, HO-2) catalyze conversion of heme to iron, carbon monoxide (CO), and biliverdin/bilirubin. We studied the effects of renal HO-1 induction on afferent arteriole (Aff-Art) autoregulatory responses to increases in renal perfusion pressure (RPP). Rats were treated with hemin and SnCl2 to induce HO-1, and Aff-Art autoregulatory responses were evaluated using the rat blood-perfused juxtamedullary nephron preparation. Renal HO-1 expression was significantly increased in hemin- and SnCl2-treated rats, while HO-2 was not altered. Aff-Art autoregulatory constrictor responses to increases in RPP from 100 to 150 mmHg were attenuated in hemin- and SnCl2-treated rats compared with control rats (+1.1 ± 3.3, n = 9 and +4.4 ± 5.3, n = 9 vs. −14.2 ± 1.5%, n = 10, respectively) (P < 0.05). Acute HO inhibition with chromium mesoporphyrin (CrMP; 15 μmol/l) restored Aff-Art autoregulatory responses in hemin- and SnCl2-treated rats. Superfusing Aff-Arts from control rats with 100 μmol/l biliverdin did not alter autoregulatory responses; however, superfusion with 1 mmol/l CO significantly attenuated autoregulatory responses to increases in RPP from 100 to 150 mmHg (+3.3 ± 5.4 vs. −16.6 ± 3.8%, n = 6) (P < 0.05). Acute soluble guanylate cyclase inhibition with 10 μmol/l ODQ restored Aff-Art autoregulatory responses in hemin-treated rats. Immunohistochemistry shows HO-2 to be expressed mainly in epithelial cells with weak staining in proximal tubules, interlobular arteries, and Aff-Arts. In hemin- and SnCl2-treated rats, HO-1 was induced in tubular epithelial cells but not interlobular arteries and Aff-Arts. We conclude that induction of renal HO-1 attenuates Aff-Art constrictor responses to increases in RPP via increasing CO production from tubular epithelial cells, suggesting that an augmented HO system in pathophysiological conditions modulates renal autoregulation

ABSTRACT: SA-OR081: Clinical Events in Type 2 Diabetes and Moderate-to-Severe CKD by Albuminuria Status: Dulaglutide vs. Insulin Glargine

BACKGROUND In participants with type 2 diabetes and moderate-to-severe chronic kidney disease (CKD), in the AWARD-7 trial, treatment with dulaglutide (DU) compared to insulin glargine (IG) led to slower estimated glomerular filtration rate (eGFR) decline at similar levels of glycemic control and blood pressure. METHODS To determine risk of a composite endpoint of ≥40% eGFR decline or end-stage kidney disease (ESKD) by albuminuria status, this post hoc analysis used Cox proportional hazards modeling for time to first event. Participants were randomized (1:1:1) to DU 0.75 mg or 1.5 mg weekly versus titrated IG daily for one year. eGFR was calculated using the CKD-epidemiology (EPI) creatinine and cystatin C equations. RESULTS At baseline, treatment groups had similar eGFR within albuminuria subgroups (Table). Through the 1-year treatment period, the majority of events occurred in patients with macroalbuminuria; the incidence rate of the composite endpoint was significantly lower for DU 1.5 mg compared to IG in those with macroalbuminuria (Table). Consistent results were obtained when eGFR was calculated using either CKD-EPI creatinine or cystatin C equations. CONCLUSION The risk of the composite endpoint of ≥40% eGFR decline or ESKD was lower by approximately half for DU 1.5 mg compared to IG, which was mainly driven by effects in participants with macroalbuminuria

Body Weight and eGFR during Dulaglutide Treatment in Type 2 Diabetes and Moderate-to-Severe Chronic Kidney Disease (AWARD-7).

In patients with T2D and moderate-to-severe CKD, dulaglutide treatment led to body weight (BW) loss and lesser eGFR decline compared to insulin glargine. Since BW may affect muscle mass, creatinine-based eGFR can be altered independent of kidney function. Cystatin C-based eGFR is not affected by muscle mass. The objective of this post-hoc analysis was to evaluate if lesser eGFR decline with dulaglutide was related to BW loss. Baseline characteristics were similar between treatments ([mean±SD] age: 64.6±8.6 years, women: 48%, BW: 89.1±17.7 kg, eGFR [CKD-EPI-cystatin C] 38±14 mL/min/1.73

Dulaglutide in Diabetes and Chronic Kidney Disease: AWARD-7 Exploratory Analysis of Clinical Outcomes

Background: In the AWARD-7 trial of participants with type 2 diabetes (T2DM) and moderate-to-severe chronic kidney disease (CKD), dulaglutide (DU) treatment slowed decline in estimated glomerular filtration rate (eGFR) compared to insulin glargine (IG). Treatment with doses of either DU or IG resulted in similar levels of glycemic control and blood pressure. The aim of this analysis was to determine the risk of clinical event outcomes between treatment groups. Methods: Participants with T2DM and CKD categories 3-4 were randomized (1:1:1) to DU 0.75 mg or 1.5 mg weekly or IG daily as basal therapy, with titrated insulin lispro, for one year. The time to occurrence of the composite outcome of ≥40% eGFR decline, end-stage kidney disease (ESKD), or death due to kidney disease was compared using a Cox proportional hazards model. Results: Patients treated with DU 1.5 mg weekly versus IG daily for 1 year had a lower risk of ≥40% eGFR decline or ESKD events in the overall study population (5.2% versus 10.8%; hazard ratio 0.45, 95% confidence interval 0.20-0.97, P=0.042). Most events occurred in the subset with macroalbuminuria, where risk of the composite outcome was substantially lower for DU 1.5 mg versus IG (7.1% versus 22.2%; hazard ratio 0.25, 95% confidence interval 0.10-0.68, P=0.006). No deaths occurred. Conclusions: Treatment with DU 1.5 mg weekly was associated with a clinically relevant risk reduction of ≥40% eGFR decline or ESKD compared to IG daily, particularly in the macroalbuminuria subgroup of participants with T2DM and moderate-to-severe CKD