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Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker.

ABSTRACT: We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treated with high-dose losartan (ARB), nonspecific antihypertensive triple-therapy (TRX), or left untreated (Control) until week 30. We found that blood pressure, serum creatinine levels, and glomerulosclerosis were lower at sacrifice in ARB and TRX vs. Control. Only ARB reduced proteinuria and maintained the density of WT-1-positive podocytes. Glomerular tufts showed more double-positive cells for CD44, a marker of activated parietal epithelial cells, and synaptopodin after ARB vs. TRX or Control. ARB treatment reduced aldosterone levels. ARB-treated rats had significantly improved survival when compared with TRX or Control. We conclude that both long-term ARB and triple-therapy ameliorate progression, but do not sustain the regression of glomerulosclerosis. ARB resulted in the superior preservation of podocyte integrity and decreased proteinuria and aldosterone, linked to increased survival in the uremic environment.

SUBMITTER: Zhu X

PROVIDER: S-EPMC9181646 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker.

Zhu Xuejing X Gao Dan D Albertazzi Vittorio V Zhong Jianyong J Ma Li-Jun LJ Du Liping L Shyr Yu Y Kon Valentina V Yang Hai-Chun HC Fogo Agnes B AB

International journal of molecular sciences 20220527 11

We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treat ...[more]

PMID: 35682697

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Project description:ObjectiveMitochondria-derived reactive oxygen species (ROS) play important roles in the development of cardiovascular disease highlighting the need for novel targeted therapies. This study assessed the potential therapeutic benefit of combining the mitochondria-specific antioxidant, MitoQ10, with the low-dose angiotensin receptor blocker (ARB), losartan, on attenuation of hypertension and left ventricular hypertrophy. In parallel, we investigated the impact of MitoQ10 on cardiac hypertrophy in a neonatal cardiomyocyte cell line.Methods and resultsEight-week-old male stroke-prone spontaneously hypertensive rats (SHRSPs, n=8-11) were treated with low-dose losartan (2.5 mg/kg per day); MitoQ10 (500 μmol/l); a combination of MitoQ10 and losartan (M+L); or vehicle for 8 weeks. Systolic pressure and pulse pressure were significantly lower in M+L rats (167.1 ± 2.9 mmHg; 50.2 ± 2.05 mmHg) than in untreated SHRSP (206.6 ± 9 mmHg, P<0.001; 63.7 ± 2.7 mmHg, P=0.001) and demonstrated greater improvement than MitoQ10 or low-dose losartan alone, as measured by radiotelemetry. Left ventricular mass index was significantly reduced from 22.8 ± 0.74 to 20.1 ± 0.61 mg/mm in the combination group (P<0.05). Picrosirius red staining showed significantly reduced cardiac fibrosis in M+L rats (0.82 ± 0.22 A.U.) compared with control (5.94 ± 1.35 A.U., P<0.01). In H9c2 neonatal rat cardiomyocytes, MitoQ10 significantly inhibited angiotensin II mediated hypertrophy in a dose-dependent manner (500 nmol/l MitoQ10 153.7 ± 3.1 microns vs. angiotensin II 200.1 ± 3.6 microns, P<0.001).ConclusionCombining MitoQ10 and low-dose losartan provides additive therapeutic benefit, significantly attenuating development of hypertension and reducing left ventricular hypertrophy. In addition, MitoQ10 mediates a direct antihypertrophic effect on rat cardiomyocytes in vitro. MitoQ10 has potential as a novel therapeutic intervention in conjunction with current antihypertensive drugs.

Project description:PurposeFimasartan, the ninth and most recent angiotensin receptor blocker (ARB) approved by the Korea Food and Drug Administration, has shown similar efficacy and safety profiles compared to other ARBs. However, due to being predominantly excreted by the hepatobiliary system, concerns on safety have been raised regarding its use in patients with underlying liver disease.Patients and methodsThis prospective, 12-month, observational study evaluated patients with essential hypertension (HTN) receiving ≥1 dose of fimasartan. Self-reported and physician-reported events were recorded and classified according to organ class and severity. Outcomes were compared according to the absence and presence of underlying liver disease.ResultsA total of 601 patients were screened, and 566 patients who met predefined inclusion criteria were grouped according to the presence of underlying liver disease. Adverse events (AE) were reported in 28.7% (128/446) of patients without prior liver disease, while 42.5% (51/120) experienced events in the group with chronic liver disease. There was no difference in discontinuations due to liver function between patients with and without baseline liver disease (1.1% [5] vs 2.5% [3], p=0.376), and only a non-significant increase was observed in events associated to the hepatobiliary system in patients with chronic liver disease (9.7% [7] vs 2.7% [9], p=0.061). There were no deaths or serious adverse drug reactions (SADR) during the study period. In multivariate regression analysis, the presence of chronic liver disease (OR 2.01), female sex (OR 1.49) and old age (OR 1.12 for every 5-year increase) were independent predictors for the development of AE. Finally, no significant difference was observed in the reduction of systolic blood pressure after 12 months of treatment (least square mean change -6.57 ± 0.80 mmHg for normal liver function group; -7.65 ± 1.59 mmHg for chronic liver disease group; p=0.546).ConclusionLong-term use of fimasartan for treatment of HTN was associated with a low rate of adverse events overall, especially in the absence of underlying liver disease. Even for patients with chronic liver disease, fimasartan treatment was well tolerated. Fimasartan could be a safe option for long-term treatment of essential HTN. ClinicalTrials.gov identifier: NCT02385721.

Project description:ImportanceThrombotic microangiopathy (TMA) on kidney biopsy is a pattern of endothelial injury commonly seen in malignant hypertension (mHTN), but treatment strategies are not well established.ObjectiveTo evaluate the kidney outcomes of angiotensin receptor-neprilysin inhibitor (ARNI), specifically sacubitril/valsartan, vs angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy for patients with mHTN-associated TMA.Design, setting, and participantsThis single-center cohort study enrolled consecutive patients in China diagnosed with mHTN-associated TMA through kidney biopsy from January 2008 to June 2023. Follow-up was conducted until the conclusion of the study period. Data were analyzed in September 2023.ExposuresTreatment with sacubitril/valsartan or ACEI/ARBs during hospitalization and after discharge.Main outcomes and measuresThe primary outcome was a composite of kidney recovery: a 50% decrease in serum creatinine level, decrease in serum creatinine levels to the reference range, or kidney survival free from dialysis for more than 1 month. The secondary and tertiary outcomes were a 15% increase in the estimated glomerular filtration rate (eGFR) relative to baseline and kidney survival free from dialysis, respectively. Propensity score matching (PSM) and Cox proportional hazards regression analysis were used to evaluate the association between sacubitril/valsartan and ACEI/ARB therapy with kidney recovery outcomes.ResultsAmong the 217 patients (mean [SD] age, 35.9 [8.8] years; 188 men [86.6%]) included in the study, 66 (30.4%) received sacubitril/valsartan and 151 (69.6%) received ACEI/ARBs at baseline. Sacubitril/valsartan treatment was associated with shorter time to the primary outcome compared with ACEI/ARB treatment (20 of 63 [31.7%] vs 38 of 117 [32.5%]; adjusted hazard ratio [aHR], 1.85; 95% CI, 1.05-3.23). Sacubitril/valsartan treatment was independently associated with shorter time to a 15% increase in eGFR (15 of 46 [32.6%] vs 46 of 83 [55.4%]; aHR, 2.13; 95% CI, 1.09-4.17) and kidney survival free from dialysis (11 of 23 [47.8%] vs 16 of 57 [28.1%]; aHR, 2.63; 95% CI, 1.15-5.88) compared with ACEI/ARB treatment. These differences remained significant in the PSM comparison.Conclusions and relevanceIn this cohort study, sacubitril/valsartan treatment was associated with a potential kidney function benefit in patients with mHTN-associated TMA compared with ACEI/ARB treatment. The findings suggested that sacubitril/valsartan could be a superior therapeutic approach for managing this serious condition in terms of kidney recovery.

Dataset Information

Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker.

Publications

Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker.

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