Acute kidney injury during pregnancy leads to increased sFlt-1 and sEng and decreased renal T regulatory cells in pregnant rats with HELLP syndrome

Abstract Background The incidence of acute kidney injury (AKI) during pregnancy precedes a high maternal mortality rate of 20–40%. AKI during pregnancy has multiple etiologies; however, the more common are maternal hypertensive disorders, which include preeclampsia and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. Therefore, we sought to assess the impact of AKI on blood pressure, kidney injury, and anti-angiogenic factors during pregnancies with and without HELLP syndrome. Methods On gestational day (GD) 12, mini-osmotic pumps were inserted into a subset of normal pregnant (NP) rats infusing 4.7 μg/kg soluble fms-like tyrosine kinase-1 (sFlt-1) and 7 μg/kg soluble endoglin (sEng) to induce HELLP syndrome. On GD18, the renal pedicles were occluded for 45 min to induce AKI via bilateral ischemia reperfusion in a subset of NP (n = 18) or HELLP (n = 20) rats. Control NP (n = 20) and HELLP (n = 20) rats underwent a SHAM surgery on GD18. Plasma, urine, and maternal organs were saved for further analysis. Renal injury was assessed via renal histopathology, glomerular filtration rate (GFR), T cell infiltration, and assessment of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Data was measured via two-way analysis of variance with Tukey’s test for post hoc analysis. Results Blood pressures were increased in HELLP+AKI rats (p = 0.0001); both NP+AKI and HELLP+AKI rats had increased lactate dehydrogenase (p < 0.0001) and aspartate aminotransferase levels (p < 0.0001), and decreased platelet levels (p < 0.001) vs. NP rats. HELLP+AKI (p = 0.002) and HELLP rats (p = 0.0002) had evidence of renal fibrosis vs. NP rats. GFR was decreased in HELLP+AKI (p = 0.01) rats vs. NP rats. Urinary KIM-1 was increased in NP+AKI rats vs. NP (p = 0.003) and HELLP rats (p = 0.01). HELLP+AKI rats had increased urinary KIM-1 vs. NP (p = 0.0008) and HELLP rats (p = 0.004) and increased NGAL vs. HELLP rats (p = 0.002). HELLP+AKI rats had increased sFlt-1 (p = 0.009) vs. NP rats. NP+AKI (p = 0.02) and HELLP+AKI (p = 0.007) rats had increased sEng vs. NP rats. CD3+CD4+ T cells were significantly increased in HELLP+AKI rats vs. NP (p = 0.0002) and NP+AKI (p = 0.05) rats. T regulatory cells were significantly decreased in HELLP+AKI (p = 0.03) and NP+AKI (p = 0.02) rats vs. NP rats; there were no changes between groups in T helper 17 cells (p = 0.34). Conclusion The findings in this study suggest that AKI during pregnancy contributes to increased blood pressure and biochemical markers for HELLP syndrome, creates an anti-angiogenic imbalance, and exacerbates kidney injury as shown on histopathology, GFR, and kidney injury markers.

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Greater T Regulatory Cells in Females Attenuate DOCA-Salt–Induced Increases in Blood Pressure Versus Males

Hypertension ◽

10.1161/hypertensionaha.119.14089 ◽

2020 ◽

Vol 75 (6) ◽

pp. 1615-1623 ◽

Cited By ~ 6

Author(s):

Kasey M. Belanger ◽

G. Ryan Crislip ◽

Ellen E. Gillis ◽

Mahmoud Abdelbary ◽

Jacqueline B. Musall ◽

...

Keyword(s):

Blood Pressure ◽

T Cells ◽

T Regulatory Cells ◽

Critical Role ◽

Kidney Injury ◽

Male Rats ◽

Regulatory Cells ◽

Salt Treatment ◽

Males And Females ◽

The Impact

Hypertension is the most common risk factor for cardiovascular disease, causing over 18 million deaths a year. Although the mechanisms controlling blood pressure (BP) in either sex remain largely unknown, T cells play a critical role in the development of hypertension. Further evidence supports a role for the immune system in contributing to sex differences in hypertension. The goal of the current study was to first, determine the impact of sex on the renal T-cell profiles in DOCA-salt hypertensive males and females and second, test the hypothesis that greater numbers of T regulatory cells (Tregs) in females protect against DOCA-salt–induced increases in BP and kidney injury. Male rats displayed greater increases in BP than females following 3 weeks of DOCA-salt treatment, although increases in renal injury were comparable between the sexes. DOCA-salt treatment resulted in an increase in proinflammatory T cells in both sexes; however, females had more anti-inflammatory Tregs than males. Additional male and female DOCA-salt rats were treated with anti-CD25 to decrease Tregs. Decreasing Tregs significantly increased BP only in females, thereby abolishing the sex difference in the BP response to DOCA-salt. This data supports the hypothesis that Tregs protect against the development of hypertension and are particularly important for the control of BP in females.

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Targeting acute kidney injury in COVID-19

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa231 ◽

2020 ◽

Vol 35 (10) ◽

pp. 1652-1662 ◽

Cited By ~ 3

Author(s):

John A Kellum ◽

J W Olivier van Till ◽

George Mulligan

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Responses ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Perfusion ◽

Endothelial Damage ◽

Acid Oxidation ◽

Acid Base ◽

The Impact ◽

Pathophysiologic Mechanisms

Abstract As of 15 August 2020, Coronavirus disease 2019 (COVID-19) has been reported in >21 million people world-wide and is responsible for more than 750,000 deaths. The occurrence of acute kidney injury (AKI) in patients hospitalized with COVID-19 has been reported to be as high as 43%. This is comparable to AKI in other forms of pneumonia requiring hospitalization, as well as in non-infectious conditions like cardiac surgery. The impact of AKI on COVID-19 outcomes is difficult to assess at present but, similar to other forms of sepsis, AKI is strongly associated with hospital mortality. Indeed, mortality is reported to be very low in COVID-19 patients without AKI. Given that AKI contributes to fluid and acid–base imbalances, compromises immune response and may impair resolution of inflammation, it seems likely that AKI contributes to mortality in these patients. The pathophysiologic mechanisms of AKI in COVID-19 are thought to be multifactorial including systemic immune and inflammatory responses induced by viral infection, systemic tissue hypoxia, reduced renal perfusion, endothelial damage and direct epithelial infection with Severe Acute Respiratory Syndrome Coronavirus 2. Mitochondria play a central role in the metabolic deregulation in the adaptive response to the systemic inflammation and are also found to be vital in response to both direct viral damage and tissue reperfusion. These stress conditions are associated with increased glycolysis and reduced fatty acid oxidation. Thus, there is a strong rationale to target AKI for therapy in COVID-19. Furthermore, many approaches that have been developed for other etiologies of AKI such as sepsis, inflammation and ischemia–reperfusion, have relevance in the treatment of COVID-19 AKI and could be rapidly pivoted to this new disease.

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Early antihypertensive treatment and ischemia-induced acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00078.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. F563-F570

Author(s):

Robert Greite ◽

Katja Derlin ◽

Bennet Hensen ◽

Anja Thorenz ◽

Song Rong ◽

...

Keyword(s):

Blood Pressure ◽

Acute Kidney Injury ◽

Antihypertensive Treatment ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Perfusion ◽

Renal Outcome ◽

Major Surgery ◽

Mesangial Matrix ◽

Matrix Expansion

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.

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Early Diabetes Aggravates Renal Ischemia/reperfusion-induced Acute Kidney Injury

10.21203/rs.3.rs-145880/v1 ◽

2021 ◽

Author(s):

Mariana de Ponte ◽

Vanessa Cardoso ◽

Juliana Costa-Pessoa ◽

Maria Oliveira-Souza

Keyword(s):

Acute Kidney Injury ◽

Risk Factor ◽

Mrna Expression ◽

Ischemia Reperfusion ◽

Kidney Tissue ◽

Kidney Injury ◽

Plasma Creatinine ◽

Ki 67 ◽

Early Diabetes ◽

The Impact

Abstract Acute kidney injury (AKI) due to ischemia and reperfusion (IR) can be associated with the progression of chronic kidney injury. In addition, studies suggest that chronic diabetes is an independent risk factor for AKI; however, the impact of early diabetes on the severity of AKI remains unknown. We investigated the effects of early diabetes on the pathophysiology of renal IR-induced AKI. C57BL/6J mice were randomly assigned into the following groups: 1) sham-operated; 2) renal IR; 3) streptozotocin (STZ - 55 mg/kg/day) and sham-operated; and 4) STZ and renal IR. On the 12th day after treatments, the animals were subjected to bilateral IR for 30 minutes followed by reperfusion for 48 hours, and the mice were euthanized by exsanguination. Renal function was assessed by analyzing the plasma creatinine and urea concentrations with biochemical methods. Proteinuria was evaluated using a commercial kit. Kidney tissue was used to evaluate the morphology, gene expression by qPCR, and protein expression by Western blotting. Compared to the sham operated, renal IR resulted in increased plasma creatinine and urea levels, decreased nephrin mRNA expression, increased tubular cast formation, and Kim-1, Ki-67, pro-inflammatory and pro-fibrotic factor mRNA expression. Compared with the sham treatment, STZ treatment resulted in hyperglycemia, but did not induce changes in kidney function or pro-inflammatory or pro-fibrotic factors. However, STZ treatment aggravated renal IR-induced AKI by exacerbating glomerular and tubular injury, inflammation, and the profibrotic response. Early diabetes constitutes a relevant risk factor for renal IR-induced AKI.

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Female and male mice have differential longterm cardiorenal outcomes following a matched degree of ischemia–reperfusion acute kidney injury

Scientific Reports ◽

10.1038/s41598-021-04701-x ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Danielle E. Soranno ◽

Peter Baker ◽

Lara Kirkbride-Romeo ◽

Sara A. Wennersten ◽

Kathy Ding ◽

...

Keyword(s):

Blood Pressure ◽

Acute Kidney Injury ◽

Mitochondrial Function ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Cardiovascular Outcomes ◽

Male Mice ◽

Male And Female ◽

Female Mice

AbstractAcute kidney injury (AKI) is common in patients, causes systemic sequelae, and predisposes patients to long-term cardiovascular disease. To date, studies of the effects of AKI on cardiovascular outcomes have only been performed in male mice. We recently demonstrated that male mice developed diastolic dysfunction, hypertension and reduced cardiac ATP levels versus sham 1 year after AKI. The effects of female sex on long-term cardiac outcomes after AKI are unknown. Therefore, we examined the 1-year cardiorenal outcomes following a single episode of bilateral renal ischemia–reperfusion injury in female C57BL/6 mice using a model with similar severity of AKI and performed concomitantly to recently published male cohorts. To match the severity of AKI between male and female mice, females received 34 min of ischemia time compared to 25 min in males. Serial renal function, echocardiograms and blood pressure assessments were performed throughout the 1-year study. Renal histology, and cardiac and plasma metabolomics and mitochondrial function in the heart and kidney were evaluated at 1 year. Measured glomerular filtration rates (GFR) were similar between male and female mice throughout the 1-year study period. One year after AKI, female mice had preserved diastolic function, normal blood pressure, and preserved levels of cardiac ATP. Compared to males, females demonstrated pathway enrichment in arginine metabolism and amino acid related energy production in both the heart and plasma, and glutathione in the plasma. Cardiac mitochondrial respiration in Complex I of the electron transport chain demonstrated improved mitochondrial function in females compared to males, regardless of AKI or sham. This is the first study to examine the long-term cardiac effects of AKI on female mice and indicate that there are important sex-related cardiorenal differences. The role of female sex in cardiovascular outcomes after AKI merits further investigation.

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Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury

Cancers ◽

10.3390/cancers13246382 ◽

2021 ◽

Vol 13 (24) ◽

pp. 6382

Author(s):

Shinji Kobuchi ◽

Miyu Kai ◽

Yukako Ito

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Dose Reduction ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Population Pharmacokinetic ◽

Time Curve ◽

Model Based ◽

Population Pk ◽

The Impact

Acute kidney injury (AKI) complicates the dosing strategies of oxaliplatin (L-OHP) and the requirement for L-OHP dose reduction in patients with renal failure remains controversial. The objective of this study is to assess the impact of AKI on the pharmacokinetics (PK) of intact L-OHP and simulate the relationship between the degree of renal function and intact L-OHP exposures using a population PK model. Intact L-OHP concentrations in plasma and urine after L-OHP administration were measured in mild and severe AKI models established in rats through renal ischemia-reperfusion. Population PK modeling and simulation were performed. There were no differences among rats in the area under the plasma concentration–time curve of intact L-OHP after intravenous L-OHP administrations. Nevertheless, the amount of L-OHP excretion after administration of 8 mg/kg L-OHP in mild and severe renal dysfunction rats was 63.5% and 37.7%, respectively, and strong correlations were observed between biochemical renal function markers and clearance of intact L-OHP. The population PK model simulated well the observed levels of intact L-OHP in AKI model rats. The population PK model-based simulation suggests that dose reduction is unnecessary for patients with mild to moderate AKI.

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Harnessing Endogenous T-Regulatory Cells in Acute Kidney Injury

Nephron ◽

10.1159/000508503 ◽

2020 ◽

Vol 144 (12) ◽

pp. 626-628

Author(s):

Rahul Sharma

Keyword(s):

Acute Kidney Injury ◽

Critical Care ◽

Intensive Care ◽

T Regulatory Cells ◽

Kidney Injury ◽

Regulatory Cells ◽

International Conference ◽

Intensive Care Patients ◽

Sizable Proportion

Acute kidney injury (AKI) affects 20–50% of hospitalized and intensive care patients, with a sizable proportion progressing to ESRD or death (https://www.kidney.org/atoz/content/AcuteKidneyInjury). Since inflammation contributes to the pathogenesis of AKI, studies on T-regulatory cells (Tregs), which suppress inflammation are important. Here, we highlight advances that utilize Tregs for intervention in AKI and were presented at the 25th International Conference on Advances in Critical Care Nephrology and UAB/UCSD O’Brien Center AKI & CRRT 2020.

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Impact of cannabidiol treatment on regulatory T-17 cells and neutrophil polarization in acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00112.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. F1149-F1158 ◽

Cited By ~ 6

Author(s):

Babak Baban ◽

Nasrul Hoda ◽

Aneeq Malik ◽

Hesam Khodadadi ◽

Erika Simmerman ◽

...

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion Injury ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

T Helper 17 ◽

Th 17 ◽

The Status ◽

Proinflammatory Responses ◽

Kidney Injury Molecule 1

Hallmark features of acute kidney injury (AKI) include mobilization of immune and inflammatory mechanisms culminating in tissue injury. Emerging information indicates heterogeneity of neutrophils with pro- and anti-inflammatory functions (N1 and N2, respectively). Also, regulatory T-17 (Treg17) cells curtail T helper 17 (Th-17)-mediated proinflammatory responses. However, the status of Treg17 cells and neutrophil phenotypes in AKI are not established. Furthermore, cannabidiol exerts immunoregulatory effects, but its impact on Treg17 cells and neutrophil subtypes is not established. Thus, we examined the status of Treg17 cells and neutrophil subtypes in AKI and determined whether cannabidiol favors regulatory neutrophils and T cells accompanied with renoprotection. Accordingly, mice were subjected to bilateral renal ischemia-reperfusion injury (IRI), without or with cannabidiol treatment; thereafter, kidneys were processed for flow cytometry analyses. Renal IRI increased N1 and Th-17 but reduced N2 and Treg17 cells accompanied with disruption of mitochondrial membrane potential (ψm) and increased apoptosis/necrosis and kidney injury molecule-1 (KIM-1) immunostaining compared with their sham controls. Importantly, cannabidiol treatment preserved ψm and reduced cell death and KIM-1 accompanied by restoration of N1 and N2 imbalance and preservation of Treg17 cells while decreasing Th-17 cells. The ability of cannabidiol to favor development of Treg17 cells was further established using functional mixed lymphocytic reaction. Subsequent studies showed higher renal blood flow and reduced serum creatinine in cannabidiol-treated IRI animals. Collectively, our novel observations establish that renal IRI causes neutrophil polarization in favor of N1 and also reduces Treg17 cells in favor of Th-17, effects that are reversed by cannabidiol treatment accompanied with significant renoprotection.

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