Atrial natriuretic peptide attenuates kidney–lung crosstalk in kidney injury

Background

Renal ischemia–reperfusion injury (IRI) is a common cause of acute kidney injury after cardiovascular surgery, which in turn deteriorates oxygenation. Atrial natriuretic peptide (ANP) has natriuretic, diuretic, and anti-inflammatory effects. To elucidate whether renal IRI induces inflammation in the kidney and lung and ANP attenuates kidney–lung crosstalk.

Materials and methods

The rats were anesthetized, tracheostomized, mechanically ventilated, and randomized to four groups: saline + IRI (n = 12), ANP + IRI (n = 12), ANP + sham (n = 6), and saline + sham (n = 6). Saline (6 mL/kg/h) or ANP (0.2 μg/kg/min) at the rate of 6 mL/kg/h was started 5 min before clamping, respectively. Renal IRI was induced by clamping the left renal pedicle for 30 min. The hemodynamics, arterial blood gases, and plasma concentrations of creatinine and lactate were measured at baseline and 1, 2, and 3 h after declamping. Lung wet-to-dry ratio was measured. The mRNA expression of tumor necrosis factor (TNF)-α, interleukin (IL) 1β, and IL-6 and histologic localization of TNF-α in the kidney and lung were measured.

Results

Renal IRI induced metabolic acidosis, pulmonary edema, increases in plasma concentrations of creatinine and lactate, and augmentation of the cytokine mRNA expression and histologic localization of TNF-α in the kidney and Renal IRI induced lung. ANP prevented IRI-induced metabolic acidosis, pulmonary edema, increases in creatinine, lactate, and the cytokine mRNA expression, attenuated histologic localization of TNF-α in the kidney and lung, and increased oxygenation.

Conclusions

ANP has renoprotective and anti-inflammatory effects on the kidney and lung in a rat model of renal IRI, suggesting that ANP attenuates kidney–lung crosstalk.     

Expression of tumor necrosis factor-α induced protein 8 like-1 in cisplatin-induced acute kidney injury models

Objective To investigate the expression and role of the tumor necrosis factor-α (TNF-α) induced protein 8 like-1 (TIPE1) in acute kidney injury (AKI) induced by cisplatin in animal model and cells. Methods Twelve male C57BL/6 mice aged 6-8 weeks were randomly divided into the control group and the model group. Mice in the model group received a single intraperitoneal injection of 20 mg/kg of cisplatin (20 mg/kg saline in the control group). All mice were euthanized after 5 days. Meanwhile, serum and kidney samples were collected. The levels of serum creatinine (Scr) and blood urea nitrogen (BUN) were detected by biochemical kits. Renal histopathological changes in mice were observed by HE staining. The expression of TIPE1 in kidney was examined using immunohistochemistry. qRT-PCR was used for testing the relative expression of TIPE1 mRNA in mice kidney. Western blotting was used for testing TIPE1 and NGAL protein relative expression in mice kidney. Human kidney proximal tubular cells (HK-2) were stimulated with 20 μmol/L cisplatin for 0, 6, 12 and 24 h to establish cisplatin-induced AKI cell model. The expressions of TIPE1 mRNA and protein were detected by qRT-PCR and Western blotting in HK-2 cells. The expression of TIPE1 gene in HK-2 cells was silenced by lentivirus containing TIPE1 siRNA sequence. Then, TIPE1 stable knockout HK-2 cell strains were treated with 20 μmol/L of cisplatin for 24 hours. The protein expression of tubular damage marker neutrophil gelatinase-associated lipocalin (NGAL), microtubule-associated protein 1 light chain 3 (LC3) and Beclin1 in HK-2 cells were detected by Western blotting. Results Compared with the control group, the expressions of TIPE1 mRNA and protein were up-regulated and NGAL protein expression was increased significantly in renal tissue of the model group (all P＜0.05). The expressions of TIPE1 mRNA and protein were remarkably increased with the prolongation of cisplatin treatment in HK-2 cells (both P＜0.05). Compared with the scramble siRNA group, the protein expressions of NGAL, LC3-Ⅱ and Beclin1 were increased significantly in the TIPE1 siRNA group after lentivirus interfered with the expression of TIPE1 gene in HK-2 cells (all P＜0.05). Conclusions The mRNA and protein expressions of TIPE1 are increased in acute kidney injury models. Gene silencing of TIPE1 can promote the expressions of early renal tubular damage marker and autophagy-related proteins, which indicates the excessive autophagy aggravates renal tubular injury. It is suggested that TIPE1 may be involved in the pathogenesis of acute kidney injury.     

Vinpocetine reduces cisplatin-induced acute kidney injury through inhibition of NF–κB pathway and activation of Nrf2/ARE pathway in rats

International Urology and Nephrology - Acute kidney injury is a complex clinical disease that is associated with a high incidence of morbidity and mortality. Drug-induced acute kidney injury occurs...     

Urinary levels of regenerating islet-derived protein III β and gelsolin differentiate gentamicin from cisplatin-induced acute kidney injury in rats

A key aspect for the clinical handling of acute kidney injury is an early diagnosis, for which a new generation of urine biomarkers is currently under development including kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin. A further diagnostic refinement is needed where one specific cause among several potentially nephrotoxic insults can be identified during the administration of multidrug therapies. In this study we identified increases in regenerating islet-derived protein III beta (reg IIIb) and gelsolin as potential differential urinary markers of gentamicin's nephrotoxicity. Indeed, urinary levels of both reg IIIb and gelsolin distinguish between the nephrotoxicity caused by gentamicin from that caused by cisplatin where these markers were not increased by the latter. Reg IIIb was found to be overexpressed in the kidneys of gentamicin-treated rats and excreted into the urine, whereas urinary gelsolin originated from the blood by glomerular filtration. Our results illustrate an etiological diagnosis of acute kidney injury through analysis of urine. Thus, our results raise the possibility of identifying the actual nephrotoxin in critically ill patients who are often treated with several nephrotoxic agents at the same time, thereby providing the potential for tailoring therapy to an individual patient, which is the aim of personalized medicine.     

Moderate hypothermia attenuates lung in flammation inlipopolysaccharide- induced acute lung injury in rats

Objective To investigate the role of moderate h.vpothennia in the lung inflammation of rat acute lung injury induced by lipopolysaccharide(LPS). Methods A rat model of acute lung injury (ALl) was established by in-tin-tracheal instillation of lipopolysaccharide ( 1.5 mg/kg, 0.5 ml) at 16 h after LPS ( 1.0 mg/kg) intraperitoneal adrninis-tmtion. Thirty-four male Sprague Dawley rats were randomly divided into four groups: control group, receiving saline only;LPS group, receiving LPS; hypothennia group, treated with hypothennia without LPS; LPS hypothennia group, treated with LPS and cooled to 32.5℃-33.0℃ as PaO2/FiO2. was below 300 mmHg. Hemodynamics and blood gases were record-ed every hour throughout the study. Rats were killed 4 h after ALl, and lung lavage was performed to measure the tumor ne-crosis factor α(TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) concentrations in bronchoalveolar lavage fluid (BALF) by using enzyme-linked immunosorbent assay (ELISA). Results PaO2/FiO2 was significantly decreased and PaCO2 was increased in the LPS group as compared to their baseline values( P＜0.01). Treatment with hypothermia inhib-ited the increase in PaCO2( P＜0.05) but had no effect on PaO2/FiO2 in the presence of LPS. The administration of LPS significantly increased the concentrations of TNF-α, IL-6 and IL-10 in BALF as compared to the control experiment( P＜0.05, P＜0.01 ). Moderate hypothermia reduced the expressions of TNF-α and IL-6 ( P＜0.01 ) but had no effect on the production of IL-10 ( P＞0.05). Conclusion Moderate hypothermia significantly inhibits proinflammatory cytokine ex-pressions in lipopolysaccharide-induced acute lung injury.     

Involvement of peroxisome proliferator–activated receptor gamma in vitamin D–mediated protection against acute kidney injury in rats

Background

Vitamin D has been reported as renoprotective agents in various studies. Recently, a few in vitro studies highlighted cross talk between vitamin D and peroxisome proliferator–activated receptor gamma (PPAR-γ). The present study investigated the activation of PPAR-γ as novel mechanism in vitamin D–mediated protection against ischemia reperfusion–induced acute kidney injury (AKI) in rats.

Materials and methods

The AKI was induced by clamping renal pedicles for 40 min followed by reperfusion for 24 h. The AKI was assessed by measuring creatinine clearance, serum urea, uric acid level, and lactate dehydrogenase activity. Moreover, serum potassium, calcium level, fractional excretion of sodium, and microproteinuria were measured in rats. The oxidative stress in renal tissues was assessed by quantification of thiobarbituric acid–reactive substances, superoxide anion generation, reduced glutathione level, and catalase and myeloperoxidase activities. The hematoxylin-eosin staining was carried out to observe histopathologic changes in renal tissues. Vitamin D (0.25, 0.5, and 1 μg/kg) was administered for 7 d before subjecting rats to renal ischemia reperfusion injury (IRI).

Results

The renal IRI in rats induced significant changes in serum, urinary, and oxidative stress parameters in renal tissues. Moreover, hematoxylin-eosin staining revealed marked damage produced by IRI in renal tissues. The administration of vitamin D at 0.5 μg/kg dose afforded maximum protection against renal IRI. The prior treatment with PPAR-γ antagonist bisphenol A diglycidyl ether significantly attenuated protective effect of vitamin D, thus confirming involvement of PPAR-γ in vitamin D–mediated renoprotection.

Conclusions

It is concluded that activation of PPAR-γ significantly contributes toward vitamin D–mediated protection against ischemia reperfusion–induced AKI.     

Defining acute kidney injury: what is the most appropriate metric?

Glomerular filtration rate (GFR) is the most widely accepted measure of kidney function. Acute kidney injury (AKI) is defined as a reduction in GFR. GFR is, however, rarely measured in clinical practice; instead, serum markers (primarily creatinine) are used to define AKI. Because serum creatinine level is not linearly related to GFR, the performance of this marker is associated with ascertainment bias and poor sensitivity. In this article we discuss the limitations and pitfalls of using serum markers to define AKI, and offer some suggestions for the future.     

Dialysis prescription in acute kidney injury: when and how much?

International Urology and Nephrology - Acute kidney injury (AKI) constitutes a serious public health problem because of its very high cost and mortality rate, with an increasing incidence,...     

Tubule-specific ablation of endogenous β-catenin aggravates acute kidney injury in mice

β-Catenin is a unique intracellular protein functioning as an integral component of the cell-cell adherens complex and a principal signaling protein mediating canonical Wnt signaling. Little is known about its function in adult kidneys in the normal physiologic state or after acute kidney injury (AKI). To study this, we generated conditional knockout mice in which the β-catenin gene was specifically disrupted in renal tubules (Ksp-β-cat-/-). These mice were phenotypically normal with no appreciable defects in kidney morphology and function. In the absence of β-catenin, γ-catenin functionally substituted for it in E-cadherin binding, thereby sustaining the integrity of epithelial adherens junctions in the kidneys. In AKI induced by ischemia reperfusion or folic acid, the loss of tubular β-catenin substantially aggravated renal lesions. Compared with controls, Ksp-β-cat-/- mice displayed higher mortality, elevated serum creatinine, and more severe morphologic injury. Consistently, apoptosis was more prevalent in kidneys of the knockout mice, which was accompanied by increased expression of p53 and Bax, and decreased phosphorylated Akt and survivin. In vitro activation of β-catenin by Wnt1 or stabilization of β-catenin protected tubular epithelial cells from apoptosis, activated Akt, induced survivin, and repressed p53 and Bax expression. Hence, endogenous β-catenin is pivotal for renal tubular protection after AKI by promoting cell survival through multiple mechanisms.     

Protective effect of 2-aminoethyl diphenylborinate on acute ischemia–reperfusion injury in the rat kidney

Background

To investigate the protective effect of 2-aminoethyl diphenylborinate (2-APB) against ischemia–reperfusion (I/R) injury in the rat kidney by an experimental study.

Materials and methods

Thirty male Sprague-Dawley rats were randomly divided into the following three groups: (1) sham group, (2) I/R group, and (3) I/R + 2-APB group. Renal I/R injury was induced by clamping the left renal pedicle for 45 min after right nephrectomy, followed by 3 h of reperfusion. The therapeutic agent 2-APB was administered intravenously at a dose of 2 mg/kg 10 min before renal ischemia. Glutathione, superoxide dismutase, total antioxidant capacity, malondialdehyde, tumor necrosis factor α, interleukin 6, aspartate aminotransferase, alanine aminotransferase, and creatinine levels were measured from blood samples, and the rats were sacrificed subsequently. Tissue samples were scored histopathologically. Visualization of apoptotic cells was performed using the terminal deoxynucleotidyl transferase dUTP nick end labeling staining method.

Results

2-APB significantly reduced serum malondialdehyde, tumor necrosis factor α, interleukin 6, aspartate aminotransferase, alanine aminotransferase, and creatinine levels in the I/R injury group. However, glutathione, superoxide dismutase, and total antioxidant capacity levels increased significantly. Histopathologic scores were significantly better and the rate of apoptosis was lower in the 2-APB group.

Conclusions

2-APB reduces oxidative stress and damage caused by renal I/R injury. The results of this study demonstrate that 2-APB can be used as an effective agent against I/R injury in the kidney.     

Could urinary kidney injury molecule-1 be a good marker in subclinical acute kidney injury in mild to moderate COVID-19 infection?

Purpose

To evaluate urinary kidney injury molecule-1 (uKIM-1), which is a proximal tubule injury biomarker in subclinical acute kidney injury (AKI) that may occur in COVID-19 infection.

Methods

The study included proteinuric (n?=?30) and non-proteinuric (n?=?30) patients diagnosed with mild/moderate COVID-19 infection between March and September 2020 and healthy individuals as a control group (n?=?20). The uKIM-1, serum creatinine, cystatin C, spot urine protein, creatinine, and albumin levels of the patients were evaluated again after an average of 21 days.

Results

The median (interquartile range) uKIM-1 level at the time of presentation was 246 (141–347) pg/mL in the proteinuric group, 83 (29–217) pg/mL in the non-proteinuric group, and 55 (21–123) pg/mL in the control group and significantly high in the proteinuric group than the others (p?<?0.001). Creatinine and cystatin C were significantly higher in the proteinuric group than in the group without proteinuria, but none of the patients met the KDIGO-AKI criteria. uKIM-1 had a positive correlation with PCR, non-albumin proteinuria, creatinine, cystatin C, CRP, fibrinogen, LDH, and ferritin, and a negative correlation with eGFR and albumin (p?<?0.05). In the multivariate regression analysis, non-albumin proteinuria (p?=?0.048) and BUN (p?=?0.034) were identified as independent factors predicting a high uKIM-1 level. After 21?±?4 days, proteinuria regressed to normal levels in 20 (67%) patients in the proteinuric group. In addition, the uKIM-1 level, albuminuria, non-albumin proteinuria, and CRP significantly decreased.

Conclusions

Our findings support that the kidney is one of the target organs of the COVID-19 and it may cause proximal tubule injury even in patients that do not present with AKI or critical/severe COVID-19 infection.

     

Functions of aquaporin 1 and α-epithelial Na+ channel in rat acute lung injury induced by acute ischemic kidney injury

Purpose

To establish a rat model of acute ischemic kidney injury by continually occluding the bilateral renal artery and renal veins, the functions of α-epithelial Na⁺ channel (α-ENaC) and aquaporin (AQP1) in lung injury induced by acute kidney injury (AKI) were examined and compared with lung injury induced by endotoxin.

Methods

Male Wistar rats were randomly divided into three groups: control group, AKI group, and sepsis group. The concentrations of AQP1 and α-ENaC in the lung tissue were detected. The concentrations of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the serum and bronchoalveolar lavage fluid were also detected.

Results

The arterial blood pH in AKI group and PaO₂ in sepsis group decreased 2 h after the experiment. A significant pulmonary interstitial and alveolar space edema, which showed a typical pathological change in acute lung injury, was found in AKI and sepsis group 8 h after the experiment. Two hours after the experiment, the concentration of TNF-α and IL-6 in the serum and bronchoalveolar lavage fluid (BALF) in AKI and sepsis group increased, whereas the pulmonary expression of AQP1 and α-ENaC decreased. The pulmonary AQP1 and α-ENaC of the rats were negatively correlated with TNF-α and IL-6 in BALF. The relevance among AQP1, α-ENaC, TNF-α, and IL-6 in sepsis group was higher than that in AKI group.

Conclusion

The TNF-α and IL-6 levels increased significantly and the pulmonary expression of AQP1 and α-ENaC declined at the early stage of AKI.     

Biomarkers of acute kidney injury in different clinical settings: a time to change the paradigm?

Acute kidney injury (AKI) is diagnosed in 5% of all hospitalized patients and in up to 50% of all ICU patients. In the last years a dramatic rise in the prevalence of AKI has been observed with virtually no change in mortality, reaching up to 50-80% in all dialyzed ICU patients. AKI may progress to end-stage renal disease, and even subclinical episodes of AKI, which are common, may also progress to end-stage renal disease. The early detection of AKI may enable timely intervention and prevention of progression; however, in animal models and in human studies the 'window of therapeutic intervention' is narrow. Different urinary and serum proteins have been intensively investigated as possible biomarkers for the early diagnosis of AKI. There are promising candidate biomarkers with the ability to detect an early and graded increase in tubular epithelial cell injury and distinguish pre-renal disease from acute tubular necrosis. In this review, new emerging biomarkers of AKI are presented and described in some clinical settings, such as cardiac surgery, contrast-induced nephropathy, delayed graft function and ICU/emergency departments, where biomarkers are urgently needed to diagnose, make prognoses and differentiate.     

Are we ready for the clinical use of novel acute kidney injury biomarkers?

Acute kidney injury (AKI) is a common event in several neonatal populations, and those neonates with AKI have poor outcomes. Serum creatinine (SCr)-based definitions of AKI are not ideal and are additionally limited in neonates whose SCr reflects the maternal creatinine level at birth and normally drops over the first weeks of life dependent on gestational age. Recent studies show that urine and serum biomarkers may provide a better basis than SCr on which to diagnose AKI. In this month's issue of Pediatric Nephrology, Sarafidis et al. show that urine neutrophil gelatinase-associated lipocalin (uNGAL), serum NGAL (sNGAL), and urine cystatin c (uCysC) are highest in those neonates with asphyxia who have elevated SCr. Furthermore, those with asphyxia without a concomitant rise in SCr levels have elevated levels of biomarkers compared to controls, suggesting a dose response. Once the SCr level returns to normal, the levels of novel AKI biomarkers continue to be elevated. While these findings strengthen the argument for the clinical use of these AKI biomarkers, further work is needed before they can be implemented in clinical practice. Large-scale observational multi-center studies are needed to test these biomarkers against hard clinical endpoints. In addition, randomized intervention trials which use biomarkers to define AKI need to be performed.     

The inflammatory response to ischemic acute kidney injury: a result of the 'right stuff' in the 'wrong place'?

PURPOSE OF REVIEW: Ischemic acute kidney injury may be exacerbated by an inflammatory response. How injury elicits inflammation remains a major question in understanding acute kidney injury. The present review examines the hypothesis that molecules released by injured cells elicit inflammation. RECENT FINDINGS: After necrotic death, intracellular molecules find their way into the extracellular space. These molecules include heat shock proteins and HMGB1. Receptors for these proteins include TLR4, TLR2, CD91 and RAGE. These proinflammatory mechanisms may be so useful that nature has evolved mechanisms for programming necrotic death via poly(ADP-ribose) polymerase and cyclophilin D. In addition, apoptosis may also elicit inflammation. SUMMARY: The concepts discussed in this review are important for clinical medicine. Drugs and genetic manipulation may ameliorate ischemic kidney injury by regulating the inflammatory response to cell injury.