Impaired angiotensin II type 1 receptor signaling contributes to sepsis-induced acute kidney injury

doi:10.1016/j.kint.2020.07.047

Kidney International

Volume 99, Issue 1, January 2021, Pages 148-160

https://doi.org/10.1016/j.kint.2020.07.047 Get rights and content

In sepsis-induced acute kidney injury, kidney blood flow may increase despite decreased glomerular filtration. Normally, angiotensin-II reduces kidney blood flow to maintain filtration. We hypothesized that sepsis reduces angiotensin type-1 receptor (AT1R) expression to account for this observation and tested this hypothesis in a patient case-control study and studies in mice. Seventy-three mice underwent cecal ligation and puncture (a sepsis model) or sham operation. Additionally, 94 septic mice received losartan (selective AT1R antagonist), angiotensin II without or with losartan, or vehicle. Cumulative urine output, kidney blood flow, blood urea nitrogen, and creatinine were measured. AT1R expression was assessed using ELISA, qPCR, and immunofluorescence. A blinded pathologist evaluated tissue for ischemic injury. AT1R expression was compared in autopsy tissue from seven patients with sepsis to that of the non-involved portion of kidney from ten individuals with kidney cancer and three non-infected but critically ill patients. By six hours post ligation/puncture, kidney blood flow doubled, blood urea nitrogen rose, and urine output fell. Concurrently, AT1R expression significantly fell 2-fold in arterioles and the macula densa. Creatinine significantly rose by 24 hours and sham operation did not alter measurements. Losartan significantly exacerbated ligation/puncture-induced changes in kidney blood flow, blood urea nitrogen, creatinine, and urine output. There was no histologic evidence of cortical ischemia. Significantly, angiotensin II prevented changes in kidney blood flow, creatinine, and urine output compared to vehicle. Co-administering losartan with angiotensin-II reversed this protection. Relative to both controls, patients with sepsis had low AT1R expression in arterioles and macula densa. Thus, murine cecal ligation/puncture and clinical sepsis decrease renal AT1R expression. Angiotensin II prevents functional changes while AT1R-blockade exacerbates them independent of ischemia in mice.

Graphical abstract

Section snippets

CLP induces changes in urine output, blood urea nitrogen, and creatinine

Urine output (Figure 1a) decreased within 6 hours of CLP (0.6 ml/kg/h vs. 2.17 ml/kg/h, 95% confidence interval [CI]: 0.29–2.78, P = 0.011). This decrease persisted at later time points and was uniformly <0.5 ml/kg/h at 18 hours post-CLP, indicating Stage II acute kidney injury by Kidney Disease improving Global Outcomes (KDIGO) criteria.¹⁴ Serum blood urea nitrogen levels were significantly elevated by 6 hours after CLP (54 mg/dl vs. 16 mg/dl; 95% CI for difference: 7–69 mg/dl, P < 0.0001) (

Discussion

In controlled animal CLP experiments and in immunohistological studies of septic human kidneys, we found evidence of decreased AT1R expression. In CLP, decreased AT1R expression appeared to contribute to the development of acute kidney injury. In particular, AT1R protein expression throughout renal cortical and vascular tissues was significantly reduced within 6 hours of CLP and persisted to 48 hours. These molecular findings chronologically aligned with the development of characteristic

Ethics statement regarding animal and human experiments

All animal studies were approved by the Institutional Animal Care and Use Committee at the Feinstein Institute for Medical Research and adhered to National Institutes of Health guidelines as well as Animal Research: Reporting of In Vivo Experiments criteria.⁴⁷ The Northwell Health Institutional Review Board determined our experiments on human tissues were review exempt.

Mice

Male C57BL/6 mice aged 12 to 14 weeks (Jackson Labs, Farmington, CT) were acclimated and maintained in a conventional,

Disclosure

MDT receives grant support from the National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS). CSD receives grant support from NIH NIGMS and is a consultant for Enlivex Therapeutics. Views expressed in this article do not necessarily represent the views of the NIH or NIGMS. All other authors declared no competing interests.

Acknowledgments

Human synthetic angiotensin II used in this study was generously provided by La Jolla Pharmaceutical Company. La Jolla Pharmaceutical Company had no access to any of the data in this study, was not involved in any part of its analysis or interpretation, and had no role in the drafting or editing of this manuscript.

We thank Richard Hotchkiss, MD, for providing human sepsis tissue specimens; Joaquin Cagliani, MD, for providing tissue samples from mice subjected to a model of hemorrhagic shock;

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Sepsis and septic shock are global healthcare problems associated with mortality rates of up to 40% despite optimal standard-of-care therapy and constitute the primary cause of death in intensive care units worldwide. Circulating biomarkers of septic shock severity may represent a clinically relevant approach to individualize those patients at risk for worse outcomes early in the course of the disease, which may facilitate early and more precise interventions to improve the clinical course. However, currently used septic shock biomarkers, including lactate, may be non-specific and have variable impact on prognosis and/or disease management. Activation of the renin-angiotensin-aldosterone system (RAAS) is likely an early event in septic shock, and studies suggest that an elevated level of renin, the early and committed step in the RAAS cascade, is a better predictor of worse outcomes in septic shock, including mortality, than the current standard-of-care measure of lactate. Despite a robust increase in renin, other elements of the RAAS, including endogenous levels of Ang II, may fail to sufficiently increase to maintain blood pressure, tissue perfusion, and protective immune responses in septic shock patients. We review the current clinical literature regarding the dysfunction of the RAAS in septic shock and potential therapeutic approaches to improve clinical outcomes.
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The role of the RAAS in different types of sepsis-induced organ injury is also debated. Decreased AT1R expression was observed in mouse kidney tissue 6 h after CLP; administration of Ang II reversed sepsis-induced kidney injury (SIAKI) via AT1R and improved creatinine level, urine output, and BUN; however, administration of losartan 6 h after CLP exacerbated SIAKI [37]. Another study found that administration of RAAS inhibitor (losartan or ramipril) 1 h after CLP attenuated the systemic inflammatory response and oxidative stress in mice, thereby improving renal function and survival [36].
Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis with high mortality but no effective treatment. The renin angiotensin (Ang) aldosterone system (RAAS) is activated in patients with sepsis but it is unclear how the Ang II/Ang II type 1 receptor (AT1R) axis contributes to SIC. This study examined the link between the Ang II/AT1R axis and SIC as well as the protective effect of AT1R blockers (ARBs). The Ang II level in peripheral plasma and AT1R expression on monocytes were significantly higher in patients with SIC compared with those in non-SIC patients and healthy controls and were correlated with the degree of myocardial injury. The ARB losartan reduced the infiltration of neutrophils, monocytes, and macrophages into the heart and spleen of SIC mice. Additionally, losartan regulated macrophage polarization from the M1 to the M2 subtype via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby maintaining the mitochondrial dynamics balance in cardiomyocytes and reducing oxidative stress and cardiomyocyte apoptosis. In conclusion, the plasma Ang II level and AT1R expression on plasma monocytes are an important biomarker in SIC. Therapeutic targeting of AT1R, for example with losartan, can potentially protect against myocardial injury in SIC.
RAS inhibition and sepsis-associated acute kidney injury
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This in turn leads to reductions in urinary output and creatinine clearance observed clinically in SA-AKI. Notably, these effects are diminished in preclinical models when angiotensin II is administered following initiation of sepsis, suggesting classical RAS activation may be beneficial during the development of SA-AKI [2,4]. From prospective studies of critically ill patients, reductions in angiotensin converting enzyme (ACE) activity, either assessed via genetic polymorphisms [5] or angiotensin I: angiotensin II peptide ratios [6], have been associated with AKI and mortality in critically ill patients.
To evaluate the effect of renin-angiotensin system (RAS) inhibiting medications prior to admission on the severity of kidney injury in patients presenting with sepsis-associated acute kidney injury (SA-AKI).
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Of 707 individuals studied, patients receiving RAS inhibition prior to admission (vs. those not) had more stage 3 AKI (40.1% vs. 28.7%; p = 0.008) and more frequently reached stage 3 AKI during the first week (49.8% vs. 41.1%; p = 0.047). In an adjusted multinomial regression model, patients receiving RAS inhibition (vs. those not) had an increased relative risk of presenting with stage 3 AKI on admission (vs. stage 1 AKI reference): RRR 2.32 (95% CI 1.50–3.59). Similar findings were observed in a propensity score matched analysis.
Patients receiving RAS inhibition (vs. those not) prior to an admission with SA-AKI presented with more severe AKI on admission and during the first week. Hospital mortality and kidney function at discharge were similar between groups.
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Basic ResearchImpaired angiotensin II type 1 receptor signaling contributes to sepsis-induced acute kidney injury

Graphical abstract

Section snippets

CLP induces changes in urine output, blood urea nitrogen, and creatinine

Discussion

Ethics statement regarding animal and human experiments

Mice

Disclosure

Acknowledgments

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

JAMA

Incidence and outcomes in acute kidney injury: a comprehensive population-based study

J Am Soc Nephrol

Early acute kidney injury and sepsis: a multicentre evaluation

Crit Care

Paradigms of acute kidney injury in the intensive care setting

Nat Rev Nephrol

Sepsis-induced acute kidney injury

Curr Opin Crit Care

Acute kidney injury in sepsis

Intensive Care Med

Renal blood flow in sepsis

Crit Care

Renal blood flow in experimental septic acute renal failure

Kidney Int

Increasing mean arterial blood pressure in sepsis: effects on fluid balance, vasopressor load and renal function

Crit Care

Renal perfusion in sepsis: from macro- to microcirculation

Kidney Int

Sepsis-induced acute kidney injury: a disease of the microcirculation

Microcirculation

Endocrine and metabolic alterations in sepsis and implications for treatment

Crit Care Clin

Sepsis: current dogma and new perspectives

Immunity

Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)

Crit Care

AT1 receptor antagonism before ischemia prevents the transition of acute kidney injury to chronic kidney disease

Kidney Int

Sepsis-induced attenuation of glucagon and 8-BrcAMP modulation of the phosphoenolpyruvate carboxykinase gene

Am J Physiol

Failed interleukin-6 signal transduction in murine sepsis: attenuation of hepatic glycoprotein 130 phosphorylation

Crit Care Med

The angiotensin II AT1 receptor-associated protein Arap1 is involved in sepsis-induced hypotension

Crit Care

Mechanisms of cardiac and renal dysfunction in patients dying of sepsis

Am J Respir Crit Care Med

Histopathology of septic acute kidney injury: a systematic review of experimental data

Crit Care Med

Renal histopathology during experimental septic acute kidney injury and recovery

Crit Care Med

Sequential analysis of a panel of biomarkers and pathologic findings in a resuscitated rat model of sepsis and recovery

Crit Care Med

Renal tubular cell mitochondrial dysfunction occurs despite preserved renal oxygen delivery in experimental septic acute kidney injury

Crit Care Med

Effects of fluid bolus therapy on renal perfusion, oxygenation, and function in early experimental septic kidney injury

Crit Care Med

Renal bioenergetics during early gram-negative mammalian sepsis and angiotensin II infusion

Intensive Care Med

Basic Research
Impaired angiotensin II type 1 receptor signaling contributes to sepsis-induced acute kidney injury