Animal Models Of Acute Kidney Injury Research Articles

Plasma Concentrations of Extracellular DNA in Acute Kidney Injury

Current diagnostic methods of acute kidney injury (AKI) have limited sensitivity and specificity. Tissue injury has been linked to an increase in the concentrations of extracellular DNA (ecDNA) in plasma. A rapid turnover of ecDNA in the circulation makes it a potential marker with high sensitivity. This study aimed to analyze the concentration of ecDNA in plasma in animal models of AKI. Three different fractions of ecDNA were measured—total ecDNA was assessed fluorometrically, while nuclear ecDNA (ncDNA) and mitochondrial DNA (mtDNA) were analyzed using quantitative real-time PCR. AKI was induced using four different murine models of AKI-bilateral ureteral obstruction (BUO), glycerol-induced AKI (GLY), ischemia–reperfusion injury (IRI) and bilateral nephrectomy (BNx). Total ecDNA was significantly higher in BUO (p < 0.05) and GLY (p < 0.05) compared to the respective control groups. ncDNA was significantly higher in BUO (p < 0.05) compared to SHAM. No significant differences in the concentrations of mtDNA were found between the groups. The plasma concentrations of different fractions of ecDNA are dependent on the mechanism of induction of AKI and warrant further investigation as potential surrogate markers of AKI.

Effect of dipeptidyl peptidase-4 inhibitors on cisplatin-induced acute nephrotoxicity in cancer patients with diabetes mellitus: A retrospective study.

BackgroundCisplatin is a highly effective chemotherapeutic agent. However, acute kidney injury (AKI) limits its subsequent use, resulting in poor cancer prognosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to attenuate cisplatin-induced AKI in animal models, but the effect in human patients remains to be clarified. We hypothesized that DPP-4 inhibitors can prevent cisplatin-induced AKI in diabetic-cancer patients.MethodsWe retrospectively reviewed all consecutive cancer patients who were treated with a first cycle of cisplatin-containing regimen between January 2011 and October 2019. We analysed data of diabetic-cancer patients treated with high-dose cisplatin (> 50 mg/m2)-containing regimens. The change of estimated glomerular filtration rate (eGFR) within 2 weeks after cisplatin treatment was compared between the patients treated with DPP-4 inhibitors and those treated without DPP-4 inhibitors.ResultsA total of 455 patients were treated with cisplatin during the period. Of these, 34 patients were eligible for the analysis. The change of eGFR was significantly less in the patients treated with DPP-4 inhibitors, compared to those without DPP-4 inhibitors [the percentages of eGFR decline (mean ± SD) was 23.6 ± 20.3% vs 43.1± 20.1%, respectively; P = 0.010]. Furthermore, the incidence of AKI was significantly less in the patients treated with DPP-4 inhibitors (25% vs 64%, respectively; P = 0.026).ConclusionsDPP-4 inhibitors may decrease the risk of cisplatin-induced AKI in diabetic patients.

RhEPO inhibited cell apoptosis to alleviate acute kidney injury in sepsis by AMPK/SIRT1 activated autophagy

BackgroundNowadays, people diagnosed sepsis may develop acute kidney injury (AKI), resulting heavy burden of health care. Recombinant human erythroprotein (rhEPO) has been suggested to have multifunction and may be used in the prevention or treatment of AKI, and its underlying mechanism remains largely unknown. MethodsIn our study, cell model induced by LPS-activated cell apoptosis in vitro and AKI animal model caused by lipopolysaccharide (LPS) injection in vivo. MTT assay and Flow Cytometry were conducted to analyze cell viability and apoptosis, respectively. Western bot was used to analyze expressions of apoptosis and autophagy associated proteins, and effects on AMPK/SIRT1 pathway. ResultsOur results suggested that rhEPO inhibited LPS-induced cell apoptosis in HK-2 and HEK-293. Moreover, we found that rhEPO activated autophagy to prevented cell apoptosis, changing the expression level of autophagy associated proteins such as LC3-I/LC3-II and P62, and AMPK/SIRT1 pathway was involved in its regulation. Additionally, both EX527 (SIRT1 inhibitor) and Compound C (AMPK inhibitor) blocked the autophagy effects caused by rhEPO and thus reversed the anti-apoptotic effects of rhEPO. Furthermore, our data demonstrated that rhEPO inhibited LPS-induced kidney tubular injury and decreased the expression level of apoptotic proteins by altering the expression level of autophagy related proteins and AMPK/SIRT1 pathway related proteins in vitro. ConclusionCollectively, rhEPO suppressed LPS-induced cell apoptosis via AMPK/SIRT1 pathway mediated autophagy, and modulating their levels may serve as potential way in preventing AKI.

Metabolomic and biochemical characterization of a new model of the transition of acute kidney injury to chronic kidney disease induced by folic acid.

BackgroundRenal diseases represent a major public health problem. The demonstration that maladaptive repair of acute kidney injury (AKI) can lead to the development of chronic kidney disease (CKD) and end-stage renal disease has generated interest in studying the pathophysiological pathways involved. Animal models of AKI–CKD transition represent important tools to study this pathology. We hypothesized that the administration of multiple doses of folic acid (FA) would lead to a progressive loss of renal function that could be characterized through biochemical parameters, histological classification and nuclear magnetic resonance (NMR) profiling.MethodsWistar rats were divided into groups: the control group received a daily intraperitoneal (I.P.) injection of double-distilled water, the experimental group received a daily I.P. injection of FA (250 mg kg body weight−1). Disease was classified according to blood urea nitrogen level: mild (40–80 mg dL−1), moderate (100–200 mg dL−1) and severe (>200 mg dL−1). We analyzed through biochemical parameters, histological classification and NMR profiling.ResultsBiochemical markers, pro-inflammatory cytokines and kidney injury biomarkers differed significantly (P < 0.05) between control and experimental groups. Histology revealed that as damage progressed, the degree of tubular injury increased, and the inflammatory infiltrate was more evident. NMR metabolomics and chemometrics revealed differences in urinary metabolites associated with CKD progression. The main physiological pathways affected were those involved in energy production and amino-acid metabolism, together with organic osmolytes. These data suggest that multiple administrations of FA induce a reproducible model of the induction of CKD. This model could help to evaluate new strategies for nephroprotection that could be applied in the clinic.

Secretomes from Mesenchymal Stem Cells against Acute Kidney Injury: Possible Heterogeneity.

A kidney has the ability to regenerate itself after a variety of renal injuries. Mesenchymal stem cells (MSCs) have been shown to ameliorate tissue damages during renal injuries and diseases. The regenerations induced by MSCs are primarily mediated by the paracrine release of soluble factors and extracellular vesicles, including exosomes and microvesicles. Extracellular vesicles contain proteins, microRNAs, and mRNAs that are transferred into recipient cells to induce several repair signaling pathways. Over the past few decades, many studies identified trophic factors from MSCs, which attenuate renal injury in a variety of animal acute kidney injury models, including renal ischemia-reperfusion injury and drug-induced renal injury, using microarray and proteomic analysis. Nevertheless, these studies have revealed the heterogeneity of trophic factors from MSCs that depend on the cell origins and different stimuli including hypoxia, inflammatory stimuli, and aging. In this review article, we summarize the secretomes and regenerative mechanisms induced by MSCs and highlight the possible heterogeneity of trophic factors from different types of MSC and different circumstances for renal regeneration.

N-(2-hydroxyphenyl)acetamide and its gold nanoparticle conjugation prevent glycerol-induced acute kidney injury by attenuating inflammation and oxidative injury in mice.

The protective activity of N-(2-hydroxyphenyl)acetamide (NA-2) and NA-2-coated gold nanoparticles (NA-2-AuNPs) in glycerol-treated model of acute kidney injury (AKI) in mice was investigated. NA-2 (50mg/kg) and NA-2-AuNPs (30mg/kg) were given to the animals for four days followed by 24-h water deprivation and injection of 50% glycerol (10ml/kg im). The animals were sacrificed on the next day. Blood and kidneys were collected for biochemical investigations (urea and creatinine), histological studies (hematoxylin and eosin; and periodic acid-Schiff staining), immunohistochemistry (actin and cyclooxygenase-2, Cox-2), and real-time RT-PCR (inducible nitric oxide synthase, iNOS; nuclear factor-κB p50, NFκB; hemeoxygenase-1, HO-1; and kidney injury molecule-1, Kim-1). NA-2 protected renal tubular necrosis and inflammation, though the result of NA-2-AuNPs was better than compound alone and it also exhibited the activity at far less dose. The test compound and its gold nano-formulation decreased the levels of serum urea and creatinine level in the treated animals. Both NA-2 and NA-2-AuNPs also conserved actin cytoskeleton, and lowered COX-2 protein expression. Moreover, the mRNA expressions of iNOS and NFkB p50 were down-regulated, and HO-1 and Kim-1 genes were up-regulated. We conclude that NA-2 and NA-2-AuNPs ameliorates kidney inflammation and injury in glycerol-induced AKI animal model via anti-oxidant and anti-inflammatory mechanisms which make it a suitable candidate for further studies. We believe that these findings will contribute in the understanding of the mechanism of action of paracetamol-like drugs and can be considered for clinical research for the prevention of AKI.

Th17 cells contribute to pulmonary fibrosis and inflammation during chronic kidney disease progression after acute ischemia.

Acute kidney injury (AKI) is associated with high mortality rates and predisposes development of chronic kidney disease (CKD). Distant organ damage, particularly in the lung, may contribute to mortality in AKI patients. Animal models of AKI demonstrate an increase in pulmonary infiltration of lymphocytes and reveal an acute compromise of lung function, but the chronic effects of AKI on pulmonary inflammation are unknown. We hypothesized that in response to renal ischemia/reperfusion (I/R), there is a persistent systemic increase in Th17 cells with potential effects on pulmonary structure and function. Renal I/R injury was performed on rats, and CKD progression was hastened by unilateral nephrectomy and exposure to 4.0% sodium diet between 35 and 63 days post-I/R. Th17 cells in peripheral blood showed a progressive increase up to 63 days after recovery from I/R injury. Infiltration of leukocytes including Th17 cells was also elevated in bronchiolar lavage (BAL) fluid 7 days after I/R and remained elevated for up to 63 days. Lung histology demonstrated an increase in alveolar cellularity and a significant increase in picrosirius red staining. Suppression of lymphocytes with mycophenolate mofetil (MMF) or an IL-17 antagonist significantly reduced Th17 cell infiltration and fibrosis in lung. In addition, tracheal smooth muscle contraction to acetylcholine was significantly enhanced 63-days after I/R relative to sham-operated controls. These data suggest that AKI is associated with a persistent increase in circulating and lung Th17 cells which may promote pulmonary fibrosis and the potential alteration in airway contractility.

Heme Oxygenase 1 as a Therapeutic Target in Acute Kidney Injury

A common clinical condition, acute kidney injury (AKI) significantly influences morbidity and mortality, particularly in critically ill patients. The pathophysiology of AKI is complex and involves multiple pathways, including inflammation, autophagy, cell-cycle progression, and oxidative stress. Recent evidence suggests that a single insult to the kidney significantly enhances the propensity to develop chronic kidney disease. Therefore, the generation of effective therapies against AKI is timely. In this context, the cytoprotective effects of heme oxygenase 1 (HO-1) in animal models of AKI are well documented. HO-1 modulates oxidative stress, autophagy, and inflammation and regulates the progression of cell cycle via direct and indirect mechanisms. These beneficial effects of HO-1 induction during AKI are mediated in part by the by-products of the HOreaction (iron, carbon monoxide, and bile pigments). This review highlights recent advances in the molecularmechanisms of HO-1-mediated cytoprotection and discusses the translational potential of HO-1 induction in AKI.

(Mesenchymal) Stem Cell-Based Therapy in Cisplatin-Induced Acute Kidney Injury Animal Model: Risk of Immunogenicity and Tumorigenicity.

Pathogenesis of AKI is complex and involves both local events in the kidney as well as systemic effects in the body that are interconnected and interdependent. Despite intensive investigations there is still no pharmacological agent that could provide complete protection against cisplatin nephrotoxicity. In the last decade mesenchymal stem cells (MSCs) have been proposed as a potentially useful therapeutic strategy in various diseases, including acute kidney injury. Although MSCs have potent immunosuppressive properties, animal studies also suggest that transplanted MSCs may elicit immune response. Interestingly, tumorigenicity of transplanted MSCs in animal studies has been rarely studied. Since the risk of tumorigenicity of particular therapy as well as the immune response to solid or cell grafts is a major issue in clinical trials, the aim of the present paper is to critically summarize the results of MSC transplantation on animal models of AKI, particularly cisplatin-induced animal models, and to expose results and main concerns about immunogenicity and tumorigenicity of transplanted MSCs, two important issues that need to be addressed in future studies.

Mitochondrial Dysfunction in Cardiorenal Syndrome.

Acute kidney injury (AKI) has a significant impact on the outcomes of critically ill patients, although no effective and specific treatment against AKI is currently available in the clinical setting. It is assumed that reactive oxygen species production by the mitochondria plays a crucial role in renal damage especially caused by cellular apoptosis. Mitochondrial injury in the heart is reported as an important determinant of myocardial contractility. Clinical epidemiological data indicate that remote organ effects induced by AKI, especially organ cross talk between the kidney and heart, might contribute to the poor outcome of AKI patients. Cardiorenal syndrome (CRS) has recently been defined based on clinical observations that acute and chronic heart failure causes kidney injury and AKI and that chronic kidney disease worsens heart diseases. Possible pathways that connect these two organs have been suggested; however, the precise mechanisms are still unclarified. Mitochondrial injury in the kidney and heart has been shown as a crucial pathway of AKI and acute heart failure by several animal studies. Clinical evidence clearly shows cardiorenal interactions in clinically ill patients, but evidence for distant organ effects of AKI on the heart is lacking. We recently found dysregulation of mitochondrial dynamics caused by increased Drp1 expression and cellular apoptosis of the heart in an experimental AKI animal model of renal ischemia-reperfusion. Precise mechanisms that induce cardiac mitochondrial injury in AKI remain unclarified. A recently suggested concept of mitochondrial hormesis may need to be considered in chronic cardiorenal interaction. Identifying the role of mitochondrial injury for CRS will enable the development of novel interventional approaches to reduce mortality associated with AKI. Antioxid. Redox Signal. 25, 200-207.

Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury.

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI.

Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition

Elucidation of acute kidney diseases and disorders (AKD), including acute kidney injury (AKI), is important to prevent their progression to chronic kidney disease. Current animal AKI models are often too severe for use in evaluating human AKI. Therefore, new animal models of mild kidney injury are needed. Here a new clinically relevant animal model using multiple low doses of cisplatin (CP) was used to evaluate AKD. When 10 mg/kg CP was administered intraperitoneally once weekly for three times to L-type fatty acid-binding protein (L-FABP) transgenic mice, moderate renal interstitial fibrosis and tubule dilatation occurred, accompanied by brush-border loss. Urinary L-FABP, a promising biomarker of AKI, changed more drastically than blood urea nitrogen or creatinine. Preventing fibrosis in organs was also studied. Oral administration of a recently reported selective semicarbazide-sensitive amine oxidase inhibitor, PXS-4728A, for 1 week attenuated kidney injury and interstitial fibrosis compared with vehicle. Inhibition of renal lipid accumulation in semicarbazide-sensitive amine oxidase inhibitor-treated mice, together with reduced oxidative stress and L-FABP suppression in proximal tubules, suggested an antifibrotic effect of semicarbazide-sensitive amine oxidase inhibition in this CP-AKD model, a representative onco-nephrology. Thus, semicarbazide-sensitive amine oxidase inhibitors may be promising candidates for the prevention of chronic kidney disease in patients using CP to treat malignancy.

Acute kidney injury.

Acute kidney injury.

Herbal Medicines for Acute Kidney Injury: Evidence, Gaps and Frontiers

Acute kidney injury (AKI) is a major health threat worldwide. The literature on herbal intervention in AKI was searched from English and Chinese databases and reports were critically analyzed in terms of preventing AKI, promoting repair and regeneration, enhancing extrarenal clearance of uremic toxins, and preventing progression to chronic kidney disease (CKD). Altogether, 16 herbal formulae and a few extracts derived from individual herbs were reported to prevent or mitigate AKI in animal models induced by renal ischemia/reperfusion, cisplastin, gentamicin, glycerol, adenine, sepsis or physical exhaustion. Four formulae and six individual herbs were reported to accelerate recovery and/ or to prevent CKD in established AKI animal models. Intrarectal herbal medicines, with or without simultaneous oral administration, were reported in six clinical trials and in an animal model to increase extrarenal clearance of uremic toxins. Additional 13 clinical trials reported oral or intravenous herbal interventions in AKI of different etiologies. Despite recurring problems, notably poor compliance with good practice guidelines for clinical trials and for authentication, naming and quality control of herbal materials, accumulating experimental data on the preventive effects of herbal medicines in AKI look encouraging and urge for better, definitive trials to guide clinical practice. Herbal enemas promoting extrarenal clearance of uremic toxins seem cost-effective, but better clinical evidence is certainly needed before any affirmative recommendation be made for AKI patients without access to dialysis. New frontiers, however, lie in those herbal remedies that promote repair/ regeneration and prevent chronicity after AKI. Recent experimental data suggest that this may be possible. Abbreviations: AKI: acute kidney injury; AKIN: Acute Kidney Injury Network; αSMA: α smooth muscle actin; ARF: acute renal failure; ATN: acute tubular necrosis; BUN: blood urea nitrogen; CAT: catalase; CKD: chronic kidney disease; CXCL12: chemokine C-X-C motif ligand 12; CXCR4: chemokine C-X-C motif receptor 4; CLP: cecal ligation and puncture; Cu-Zn-SOD: copper-zinc superoxide dismutase; ECM: extracellular matrix; eGFR: estimated glomerular filtration rate; EMT: epithelial-to-mesenchymal transition; ESWL: extracorporeal shock wave lithotripsy; FSP: fibroblast-specific protein 1; GSH: glutathione; GSH-Px: glutathione peroxidase; HMP: herbal medicinal product; HO-1: heme oxygenase 1; ICAM-1: intercellular adhesion molecule-1; ICU: intensive care unit; IFN-γ: interferonγ; IL: interleukin; iNOS: inducible nitric oxide synthase; i.p.: intraperitoneally or intraperitoneal; I/R: ischemia/reperfusion; i.v.: intravenous or intravenously; JNK: c-Jun N-terminal kinase; KDIGO: Kidney Disease Improving Global Outcomes; KIM-1: kidney injury molecule 1; LPS: lipopolysaccharides; MCP-1: monocyte chemotactic protein 1; MDA: malondialdehyde; MMP9: matrix metalloproteinase 9; Mn-SOD: manganese superoxide dismutase; NF-κB: nuclear factor κB; NGAL: neutrophil gelatinase-associated lipocalin; NO: nitric oxide; PCI: percutaneous coronary intervention; PCNA: proliferating cell nuclear antigen; p.o.: per os (oral administration); pRIFLE: modified RIFLE guideline for pediatric use; RCT: randomized controlled clinical trial; ROS/RNS: reactive oxygen/nitrogen species; RIFLE: Risk, Injury, Failure, Loss, and End-stage renal disease; RPTECs: renal proximal tubular epithelial cells; Scr: serum creatinine; TCM: traditional Chinese medicine; TGF-β: transforming growth factor β; TIMP1: tissue inhibitor of metalloproteinase 1; TNF-α: tumor necrosis factor-α; UUO: unilateral ureteral obstruction.

Acute kidney injury after cardiac surgery: is minocycline protective?

Acute kidney injury (AKI) after cardiac bypass surgery (CABG) is common and carries a significant association with morbidity and mortality. Since minocycline therapy attenuates kidney injury in animal models of AKI, we tested its effects in patients undergoing CABG. This is a randomized, double-blinded, placebo-controlled, multi-center study. We screened high risk patients who were scheduled to undergo CABG in two medical centers between Jan 2008 and June 2011. 40 patients were randomized and 19 patients in each group completed the study. Minocycline prophylaxis was given twice daily, at least for four doses prior to CABG. Primary outcome was defined as AKI [0.3 mg/dl increase in creatinine (Cr)] within 5 days after surgery. Daily serum Cr for 5 days, various clinical and hemodynamic measures and length of stay were recorded. The two groups had similar baseline and intra-operative characteristics. The primary outcome occurred in 52.6% of patients in the minocycline group as compared to 36.8% of patients in the placebo group (p = 0.51). Peak Cr was 1.6 ± 0.7 vs. 1.5 ± 0.7 mg/dl (p = 0.45) in minocycline and placebo groups, respectively. Death at 30 days occurred in 0 vs. 10.5% in the minocycline and placebo groups, respectively (p = 0.48). There were no differences in post-operative length of stay, and cardiovascular events between the two groups. There was a trend towards lower diastolic pulmonary artery pressure [16.8 ± 4.7 vs. 20.7 ± 6.6 mmHg (p = 0.059)] and central venous pressure [11.8 ± 4.3 vs. 14.6 ± 5.6 mmHg (p = 0.13)] in the minocycline group compared to placebo on the first day after surgery. Minocycline did not protect against AKI post-CABG.

Potential amelioration of upregulated renal HIF-1alpha–endothelin-1 system by landiolol hydrochloride in a rat model of endotoxemia

AimsEndothelin (ET)-1 is the best known potent vasoconstrictor and has been implicated in pathogenesis of sepsis-associated acute kidney injury (AKI) in human or lipopolysaccharide (LPS)-induced AKI in animal models. We have previously shown that ET-1 is highly up-regulated in renal tissues and in plasma after LPS administration. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting beta-blocker, can play an important role in ameliorating levels of LPS-induced up-regulation of renal HIF-1α–ET-1 system and inflammatory cytokines in a rat model of endotoxemia. Main methodsMale Wistar rats at 8weeks of age were either administered with: a) lipopolysaccharide (LPS) only for three hours (3h) or b) LPS, followed by continuous administration of landiolol for 3h; c) third group was only treated with vehicle. Key findingsAt 3h after LPS administration there was: a) minimal injury in kidney tissues; b) circulatory levels of creatinine, blood urea nitrogen and NGAL increased and c) expression of inflammatory cytokines, such as TNF-α, IL-6 and iNOS increased at the level of both circulatory and renal tissues. In addition, LPS significantly induced renal expression of ET-1 and HIF-1α compared to control. Finally, treatment of LPS-administered rats with landiolol for 3h normalized elevated serum markers of renal injury and up-regulated levels of renal HIF-1α–ET-1 system with normalization of TNF-α. SignificanceTaken together, these data led us to conclude that landiolol ameliorates the up-regulation of HIF-1α–ET-1 system in minimally morphologically-injured kidney and normalizes biomarkers of renal injury in early hours of endotoxemia of a rat model.

Megalin in acute kidney injury: foe and friend

The kidney proximal tubule is a key target in many forms of acute kidney injury (AKI). The multiligand receptor megalin is responsible for the normal proximal tubule uptake of filtered molecules, including nephrotoxins, cytokines, and markers of AKI. By mediating the uptake of nephrotoxins, megalin plays an essential role in the development of some types of AKI. However, megalin also mediates the tubular uptake of molecules implicated in the protection against AKI, and changes in megalin expression have been demonstrated in AKI in animal models. Thus, modulation of megalin expression in response to AKI may be an important part of the tubule cell adaption to cellular protection and regeneration and should be further investigated as a potential target of intervention. This review explores current evidence linking megalin expression and function to the development, diagnosis, and progression of AKI as well as renal protection against AKI.

Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis

Chronic kidney disease (CKD) remains one of the leading causes of death in the developed world and acute kidney injury (AKI) is now recognized as a major risk factor in its development. Understanding the factors leading to CKD after acute injury are limited by current animal models of AKI which concurrently target various kidney cell types such as epithelial, endothelial and inflammatory cells. Here we developed a mouse model of kidney injury using the Six2-Cre-LoxP technology to selectively activate expression of the simian diphtheria toxin receptor in renal epithelia derived from the metanephric mesenchyme. By adjusting the timing and dose of diphtheria toxin a highly selective model of tubular injury was created to define the acute and chronic consequences of isolated epithelial injury. The diphtheria toxin-induced sublethal tubular epithelial injury was confined to the S1 and S2 segments of the proximal tubule rather than being widespread in the metanephric mesenchyme derived epithelial lineage. Acute injury was promptly followed by inflammatory cell infiltration and robust tubular cell proliferation leading to complete recovery after a single toxin insult. In striking contrast, three insults to renal epithelial cells at one week intervals resulted in maladaptive repair with interstitial capillary loss, fibrosis and glomerulosclerosis which was highly correlated with the degree of interstitial fibrosis. Thus, selective epithelial injury can drive the formation of interstitial fibrosis, capillary rarefaction and potentially glomerulosclerosis, substantiating a direct role for damaged tubule epithelium in the pathogenesis of CKD.

Role of leukocytes in the pathogenesis of acute kidney injury

Acute kidney injury (AKI) is a significant cause of morbidity and mortality in hospitalized patients, especially those who are critically ill. The mortality rate in patients with severe AKI requiring renal replacement therapy (RRT) can exceed 50 % [1]. Numerous factors contribute to the development of AKI, including reductions in renal blood flow, actions of nephrotoxic drugs, cellular injury/death of proximal tubule epithelial cells, pro-inflammatory responses of renal endothelial cells, influx and activation of inflammatory leukocytes that further reduces renal blood flow through vascular congestion and promotes and extends injury to kidney parenchymal cells [2, 3]. The immune response in AKI involves cells of both the innate and adaptive immune systems. Although numerous studies have demonstrated the detrimental role of many different types of immune cells, recent reports have uncovered a protective and possibly therapeutic role of other immune cells in AKI. Studies in animal models of AKI have revealed that innate immune cells, such as neutrophils, macrophages, dendritic cells, natural killer (NK) cells and natural killer T (NKT) cells, and adaptive CD4+ T cells promote renal injury. Indeed, renal inflammation is a common feature of human AKI [4] and detailed analyses of biopsy samples from patients with AKI demonstrated the presence of mononuclear leukocytes (some CD3+ T cells) and neutrophils [5]. In contrast, CD4+FoxP3+ regulatory T cells (Tregs) can protect the kidney from ischemic and nephrotoxic injury in animal models.

Urinary L-type fatty acid-binding protein as a new renal biomarker in critical care

Acute kidney injury (AKI) remarkably increases the mortality of critically ill patients treated in ICUs. Recently, several renal biomarkers have been developed for the early detection of AKI. We review the potential of urinary L-type fatty acid-binding protein (L-FABP) as a new renal biomarker for AKI diagnosis in critical care. In the kidney, L-FABP is expressed in renal proximal tubular epithelial cells and shed into urine rapidly in response to renal insults. By using human L-FABP transgenic mice, we reported that urinary L-FABP can detect AKI sensitively and reflect its severity accurately in animal models of AKI and sepsis. In clinical evaluations, the good performance of urinary L-FABP was demonstrated not only in pediatric postcardiopulmonary bypass surgery AKI and contrast media-induced AKI but also in septic shock patients complicated with AKI. Recent data suggest that urinary L-FABP can contribute to the development of new AKI diagnostic tools in critical care. Combining with other renal markers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), optimal threshold determination for distinguishing AKI from chronic renal failure should be explored before translation to the clinical.