High-expression of FABP4 in Tubules is a Risk Factor for Poor Prognosis in DKD Patients.

BACKGROUND: Lipid metabolism imbalance is involved in the mechanism of renal tubular injury in diabetic kidney disease (DKD). Fatty acid binding protein 4 (FABP4) has been reported to participate in cellular lipid toxicity. However, the expression of FABP4 in renal tissues of DKD and its correlation with clinical/ pathological parameters and prognosis have not been studied. METHODS: A retrospective cohort study was conducted in 108 hospitalized Type 2 diabetes (T2D) patients with renal injury, including 70 with DKD and 38 with NDKD (non-DKD). Clinical features, pathological findings, and follow-up parameters were collected. Serum and urine FABP4 were detected by ELISA. An immunohistochemistry stain was used to determine FABP4 in renal tubulointerstitium. A double immunofluorescence stain was employed to assess FABP4- and CD68-positive macrophages. Correlation analysis, logistic regression models, receiver operating characteristic (ROC), and Kaplan-Meier survival curve were performed for statistical analysis. RESULTS: DKD patients had increased expression of FABP4 and ectopic fat deposition in tubules. As shown by correlation analyses, FABP4 expression in renal tubules was positively correlated with UNAG (r=0.589, p=0.044) and ESRD (r=0.740, p=0.004). Multivariate regression analysis revealed that UNAG level was correlated with FABP4 expression level above median value (odds ratio:1.154, 95% confidence interval:1.009-1.321, p=0.037). High-expression of FABP4 in renal tubules of DKD was at an increased risk of ESRD. Increased FABP4 expression in inflammatory cells was also associated with ESRD in DKD. CONCLUSION: High-expression of FABP4 is involved in the pathogenesis of renal tubular lipid injury and is a risk factor for poor prognosis in DKD patients.

New insights in the renal distribution profile of TRPC3 - Of mice and men.

Several reports previously investigated the Transient Receptor Potential Canonical subfamily channel 3 (TRPC3) in the kidney. However, most of the conclusions are based on animal samples or cell cultures leaving the door open for human tissue investigations. Moreover, results often disagreed among investigators. Histological description is lacking since most of these studies focused on functional aspects. Nevertheless, the same reports highlighted the potential key-role of TRPC3 in renal disorders. Hence, our interest to investigate the localization of TRPC3 in human kidneys. For this purpose, both healthy mouse and human kidney samples that were originated from tumor nephrectomies have been prepared for immunohistochemical staining using a knockout-validated antibody. A blocking peptide was used to confirm antibody specificity. A normalized weighted diaminobenzidine (DAB) area score between 0 and 3 comparable to a pixelwise H-score was established and employed for semiquantitative analysis. Altogether, our results suggest that glomeruli only express little TRPC3 compared to several segments of the tubular system. Cortical and medullary proximal tubules are stained, although intracortical differences in staining exist in mice. Intermediate tubules, however, are only weakly stained. The distal tubule was studied in three localizations and staining was marked although slightly varying throughout the different subsegments. Finally, the collecting duct was also immunolabeled in both human and mouse tissue. We therefore provide evidence that TRPC3 is expressed in various localizations of both human and mouse samples. We verify results of previous studies and propose until now undescribed localizations of TRPC3 in the mouse but especially and of greater interest in the human kidney. We thereby not only support the translational concept of the TRPC3 channel as key-player in physiology and pathophysiology of the human kidney but also present new potential targets to functional analysis.

Renal macrophages monitor and remove particles from urine to prevent tubule obstruction.

When the filtrate of the glomerulus flows through the renal tubular system, various microscopic sediment particles, including mineral crystals, are generated. Dislodging these particles is critical to ensuring the free flow of filtrate, whereas failure to remove them will result in kidney stone formation and obstruction. However, the underlying mechanism for the clearance is unclear. Here, using high-resolution microscopy, we found that the juxtatubular macrophages in the renal medulla constitutively formed transepithelial protrusions and "sampled" urine contents. They efficiently sequestered and phagocytosed intraluminal sediment particles and occasionally transmigrated to the tubule lumen to escort the excretion of urine particles. Mice with decreased renal macrophage numbers were prone to developing various intratubular sediments, including kidney stones. Mechanistically, the transepithelial behaviors of medulla macrophages required integrin ß1-mediated ligation to the tubular epithelium. These findings indicate that medulla macrophages sample urine content and remove intratubular particles to keep the tubular system unobstructed.

The Molecular Mechanism of Renal Tubulointerstitial Inflammation Promoting Diabetic Nephropathy.

Diabetic nephropathy (DN) is a common complication affecting many diabetic patients, leading to end-stage renal disease. However, its pathogenesis still needs to be fully understood to enhance the effectiveness of treatment methods. Traditional theories are predominantly centered on glomerular injuries and need more explicit explanations of recent clinical observations suggesting that renal tubules equally contribute to renal function and that tubular lesions are early features of DN, even occurring before glomerular lesions. Although the conventional view is that DN is not an inflammatory disease, recent studies indicate that systemic and local inflammation, including tubulointerstitial inflammation, contributes to the development of DN. In patients with DN, intrinsic tubulointerstitial cells produce many proinflammatory factors, leading to medullary inflammatory cell infiltration and activation of inflammatory cells in the interstitial region. Therefore, understanding the molecular mechanism of renal tubulointerstitial inflammation contributing to DN injury is of great significance and will help further identify key factors regulating renal tubulointerstitial inflammation in the high glucose environment. This will aid in developing new targets for DN diagnosis and treatment and expanding new DN treatment methods.

A sub-10-nm, folic acid-conjugated gold nanoparticle as self-therapeutic treatment of tubulointerstitial fibrosis.

Nanomedicines for treating chronic kidney disease (CKD) are on the horizon, yet their delivery to renal tubules where tubulointerstitial fibrosis occurs remains inefficient. We report a folic acid-conjugated gold nanoparticle that can transport into renal tubules and treat tubulointerstitial fibrosis in mice with unilateral ureteral obstruction. The 3-nm gold core allows for the dissection of bio-nano interactions in the fibrotic kidney, ensures the overall nanoparticle (~7 nm) to be small enough for glomerular filtration, and naturally inhibits the p38α mitogen-activated protein kinase in the absence of chemical or biological drugs. The folic acids support binding to selected tubule cells with overexpression of folate receptors and promote retention in the fibrotic kidney. Upon intravenous injection, this nanoparticle can selectively accumulate in the fibrotic kidney over the nonfibrotic contralateral kidney at ~3.6% of the injected dose. Delivery to the fibrotic kidney depends on nanoparticle size and disease stage. Notably, a single injection of this self-therapeutic nanoparticle reduces tissue degeneration, inhibits genes related to the extracellular matrix, and treats fibrosis more effectively than standard Captopril therapy. Our data underscore the importance of constructing CKD nanomedicines based on renal pathophysiology.

Calcium oxalate crystal-induced secretome derived from proximal tubular cells, not that from distal tubular cells, induces renal fibroblast activation.

BACKGROUND: Kidney stone disease (KSD) is commonly accompanied with renal fibrosis, characterized by accumulation and reorganization of extracellular matrix (ECM). During fibrogenesis, resident renal fibroblasts are activated to become myofibroblasts that actively produce ECM. However, such fibroblast-myofibroblast differentiation in KSD remained unclear. Our present study thus examined effects of secreted products (secretome) derived from proximal (HK-2) vs. distal (MDCK) renal tubular cells exposed to calcium oxalate monohydrate (COM) crystals on activation of renal fibroblasts (BHK-21). METHODS: HK-2 and MDCK cells were treated with 100 µg/ml COM crystals under serum-free condition for 16 h. In parallel, the cells maintained in serum-free medium without COM treatment served as the control. Secretome derived from culture supernatant of each sample was mixed (1:1) with fresh serum-free medium and then used for BHK-21 culture for another 24 h. RESULTS: Analyses revealed that COM-treated-HK-2 secretome significantly induced proliferation, caused morphological changes, increased spindle index, and upregulated fibroblast-activation markers (F-actin, α-SMA and fibronectin) in BHK-21 cells. However, COM-treated-MDCK secretome had no significant effects on these BHK-21 parameters. Moreover, level of transforming growth factor-ß1 (TGF-ß1), a profibrotic factor, significantly increased in the COM-treated-HK-2 secretome but not in the COM-treated-MDCK secretome. CONCLUSIONS: These data indicate, for the first time, that proximal and distal tubular epithelial cells exposed to COM crystals send different messages to resident renal fibroblasts. Only the secretome derived from proximal tubular cells, not that from the distal cells, induces renal fibroblast activation after their exposure to COM crystals. Such differential effects are partly due to TGF-ß1 secretion, which is induced by COM crystals only in proximal tubular cells.

The metabolites of de novo NAD+ synthesis are a valuable predictor of acute kidney injury.

Background: Acute kidney injury (AKI) is often iatrogenic and potentially preventable. Reduced renal nicotinamide adenine dinucleotide (NAD+) is reported to increase the susceptibility of AKI. The present study explored the predictive value of urinary de novo NAD+ synthetic metabolites for AKI using two independent cohorts. Methods: The expression of de novo NAD+ synthetic enzymes in human kidney was examined by immunohistochemistry and single-cell transcriptomes. Urine samples were collected from two independent cohorts: the methotrexate (MTX) cohort with high-dose MTX treatment for lymphoma (n = 189) and the liver transplantation cohort with orthotopic liver transplantation (n = 49). Urinary metabolomics study of NAD+ de novo synthesis was performed by liquid chromatography with mass spectrometry, screening for AKI predictive biomarkers. Nephroseq database and immunohistochemistry were used to analyze kidney de novo NAD+ synthetic enzymes expression in AKI-susceptible conditions. Results: Human proximal tubule was the main structure in the kidney that expressed the necessary enzymes for NAD+ de novo synthesis. In the MTX cohort, the urinary quinolinic acid (QA)/3-hydroxyanthranilic acid (3-OH AA) ratio before chemotherapy was significantly lower in those who developed AKI after chemotherapy compared with those who did not. This finding was consistent in the liver transplantation cohort. The area under the receiver-operating characteristic curve (AUC) of urinary QA/3-OH AA for AKI prediction was 0.749 and 0.729 in two cohorts, respectively. 3-Hydroxyanthranilic acid dioxygenase (HAAO), the enzyme catalyzing QA synthesis from 3-OH AA, decreased in AKI-susceptible diabetic kidneys. Conclusions: The human proximal tubules were important source of NAD+ from the de novo pathway. Reduced urinary QA/3-OH AA ratio, which possibly suggested decreased HAAO activity, could be a potential AKI predictive biomarker.

FTIR Analysis of Renal Tissue for the Assessment of Hypertensive Organ Damage and proANP31-67 Treatment.

The kidneys are one of the main end organs targeted by hypertensive disease. Although the central role of the kidneys in the regulation of high blood pressure has been long recognized, the detailed mechanisms behind the pathophysiology of renal damage in hypertension remain a matter of investigation. Early renal biochemical alterations due to salt-induced hypertension in Dahl/salt-sensitive rats were monitored by Fourier-Transform Infrared (FTIR) micro-imaging. Furthermore, FTIR was used to investigate the effects of proANP31-67, a linear fragment of pro-atrial natriuretic peptide, on the renal tissue of hypertensive rats. Different hypertension-induced alterations were detected in the renal parenchyma and blood vessels by the combination of FTIR imaging and principal component analysis on specific spectral regions. Changes in amino acids and protein contents observed in renal blood vessels were independent of altered lipid, carbohydrate, and glycoprotein contents in the renal parenchyma. FTIR micro-imaging was found to be a reliable tool for monitoring the remarkable heterogeneity of kidney tissue and its hypertension-induced alterations. In addition, FTIR detected a significant reduction in these hypertension-induced alterations in the kidneys of proANP31-67-treated rats, further indicating the high sensitivity of this cutting-edge imaging modality and the beneficial effects of this novel medication on the kidneys.

Fluid-structure interaction modelling of neighboring tubes with primary cilium analysis.

We have developed a numerical model of two osculating cylindrical elastic renal tubules to investigate the impact of neighboring tubules on the stress applied to a primary cilium. We hypothesize that the stress at the base of the primary cilium will depend on the mechanical coupling of the tubules due to local constrained motion of the tubule wall. The objective of this work was to determine the in-plane stresses of a primary cilium attached to the inner wall of one renal tubule subject to the applied pulsatile flow, with a neighboring renal tube filled with stagnant fluid in close proximity to the primary tubule. We used the commercial software COMSOLⓇ to model the fluid-structure interaction of the applied flow and tubule wall, and we applied a boundary load to the face of the primary cilium during this simulation to produces a stress at its base. We confirm our hypothesis by observing that on average the in-plane stresses are greater at the base of the cilium when there is a neighboring renal tube versus if there is no neighboring tube at all. In combination with the hypothesized function of a cilium as a biological fluid flow sensor, these results indicate that flow signaling may also depend on how the tubule wall is constrained by neighboring tubules. Our results may be limited in their interpretation due to the simplified nature of our model geometry, and further improvements to the model may potentially lead to the design of future experiments.

Potential Novel Role of Membrane-Associated Carbonic Anhydrases in the Kidney.

Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO2) and water into bicarbonate (HCO3-) and protons (H+), thereby influencing pH, are near the core of virtually all physiological processes in the body. In the kidneys, soluble and membrane-associated CAs and their synergy with acid-base transporters play important roles in urinary acid secretion, the largest component of which is the reabsorption of HCO3- in specific nephron segments. Among these transporters are the Na+-coupled HCO3- transporters (NCBTs) and the Cl--HCO3- exchangers (AEs)-members of the "solute-linked carrier" 4 (SLC4) family. All of these transporters have traditionally been regarded as "HCO3-" transporters. However, recently our group has demonstrated that two of the NCBTs carry CO32- rather than HCO3- and has hypothesized that all NCBTs follow suit. In this review, we examine current knowledge on the role of CAs and "HCO3-" transporters of the SLC4 family in renal acid-base physiology and discuss how our recent findings impact renal acid secretion, including HCO3- reabsorption. Traditionally, investigators have associated CAs with producing or consuming solutes (CO2, HCO3-, and H+) and thus ensuring their efficient transport across cell membranes. In the case of CO32- transport by NCBTs, however, we hypothesize that the role of membrane-associated CAs is not the appreciable production or consumption of substrates but the minimization of pH changes in nanodomains near the membrane.

Improvement in Renal Function During the Treatment of Acute Decompensated Heart Failure: Relationship With Markers of Renal Tubular Injury and Prognostic Importance.

BACKGROUND: Improvement in renal function (IRF) in acute decompensated heart failure is associated with adverse outcomes. The mechanisms driving this paradox remain undefined. METHODS: Using the ROSE-AHF study (Renal Optimization Strategies Evaluation-Acute Heart Failure), 277 patients were grouped according to renal function, with IRF defined by a ≥20% increase (N=75), worsening renal function by a ≥20% decline (N=53), and stable renal function (SRF) by a <20% change (N=149) in estimated glomerular filtration rate between baseline and 72 hours. Three well-validated renal tubular injury markers, NGAL (neutrophil gelatinase-associated lipocalin), NAG (N-acetyl-ß-d-glucosaminidase), and KIM-1 (kidney injury molecule 1), were evaluated at baseline and 72 hours. Patients were also classified by the pattern of change in these markers. RESULTS: Patients with IRF had the lowest admission estimated glomerular filtration rate (IRF, 37 [28 to 51] mL/min per 1.73 m2; worsening renal function, 43 [35 to 55] mL/min per 1.73 m2; and SRF, 43 [32 to 55] mL/min per 1.73 m2; Ptrend=0.032) but greater cumulative urine output (IRF, 8780 [7025 to 11 208] mL; worsening renal function, 7860 [5555 to 9765] mL; and SRF, 8150 [6325 to 10 456] mL; Ptrend=0.024) and weight loss (IRF, -9.0 [-12.4 to -5.3] lb; worsening renal function, -5.1 [-8.1 to -1.3] lb; and SRF, -7.1 [-11.9 to -3.2] lb; Ptrend<0.001) despite similar diuretic doses (Ptrend=0.16). There were no differences in the relative change in NGAL, NAG, or KIM-1 between renal function groups (Ptrend>0.19 for all). Patients with IRF had worse survival than patients with SRF (27% versus 54%; hazard ratio, 1.98 [1.10-3.58]; P=0.024). CONCLUSIONS: IRF during decongestive therapy for acute decompensated heart failure was not associated with improved markers of renal tubular injury and was associated with worsened survival, likely driven by the presence of greater underlying cardiorenal dysfunction and more severe congestion.

The Effect of Body Mass Index on the Degree of Renal Interstitial Fibrosis and Tubular Atrophy - A Retrospective Case-Control Study.

Introduction The degree of interstitial fibrosis and tubular atrophy (IFTA) seen on kidney biopsy has long been used to judge the chronicity of kidney disease to predict renal disease outcomes and prognosis. It is an essential component incorporated in many renal disease prognostic classification systems on the native and renal allograft. The impact of increased body mass index on the body metabolism, and the human vascular system, including the functional unit of the kidney, the nephron, is well-addressed in the literature. In this study, we focus on evaluating the degree of IFTA concerning the patient's body mass index (BMI). Method All the specimens of nephrectomies performed in King Abdulaziz University Hospital for adults from January 2010 to February 2021 were evaluated for this study. A total of 125 cases were selected for the study. The glass slides were pulled and assessed for the degree of IFTA. The demographic data, and the patient's BMI, were collected from the hospital records. Results Subjects with high BMI showed a 1.62 (OR: 1.62, 95% CI: 0.62, 4.22) and 1.52 (AOR: 1.52, 95% CI: 0.56, 4.13) increased risk of high IFTA score compared with those with normal BMI. This study has proved that only at a BMI of 25 or more will there be a measurable, independent effect on the degree of IFTA. Conclusion Although a small number of hospital-based populations limits this study, it could prove the increased severity of IFTA in patients with high BMI. Its result may act as a spark that will drive extensive population-based studies that more precisely delineate the relationship between BMI and the degree of IFTA on different levels.

Immune-related SERPINA3 as a biomarker involved in diabetic nephropathy renal tubular injury.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and has become a serious medical issue globally. Although it is known to be associated with glomerular injury, tubular injury has been found to participate in DN in recent years. However, mechanisms of diabetic renal tubular injury remain unclear. Here, we investigated the differentially expressed genes in the renal tubules of patients with DN by analyzing three RNA-seq datasets downloaded from the Gene Expression Omnibus database. Gene set enrichment analysis and weighted gene co-expression network analysis showed that DN is highly correlated with the immune system. The immune-related gene SERPINA3 was screened out with lasso regression and Kaplan-Meier survival analyses. Considering that SERPINA3 is an inhibitor of mast cell chymase, we examined the expression level of SERPINA3 and chymase in human renal tubular biopsies and found that SERPINA3 was upregulated in DN tubules, which is consistent with the results of the differential expression analysis. Besides, the infiltration and degranulation rates of mast cells are augmented in DN. By summarizing the biological function of SERPINA3, chymase, and mast cells in DN based on our results and those of previous studies, we speculated that SERPINA3 is a protective immune-related molecule that prevents renal tubular injury by inhibiting the proliferation and activation of mast cells and downregulating the activity of chymase.

Ochratoxin A induced differentiation nephrotoxicity in renal tubule and glomeruli via autophagy differential regulation.

Ochratoxin A (OTA) is a mycotoxin that mainly causes nephrotoxicity. The single nephrotoxicity of OTA exposure on glomeruli or renal tubule had been well documented, however, the comparison toxicity between it is still unclear. Here, C57BL/6 mice and two types of nephrocyte were treated with concentration-gradient OTA to explore its differentiation nephrotoxicity. Results showed that OTA induced nephrotoxicity in vivo and in vitro, manifested as the deteriorative kidney function in mice and the cut-down cell viability in nephrocyte. Besides, results of murine kidney pathological section and IC50 of two types nephrocyte indicated that OTA-induced toxicity in renal tubule was higher than its in glomeruli. In addition, OTA exposure induced autophagy signaling differentiation expression. It revealed that autophagy was implicated in OTA-induced differential nephrotoxicity in glomeruli and renal tubule. Altogether, we proved that OTA induces a differentiation nephrotoxicity in glomeruli and renal tubule, and it is related to autophagy differential regulation.

C5b-9 mediates ferroptosis of tubular epithelial cells in trichloroethylene-sensitization mice.

Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) is a key but unresolved question. OMDT patients often present multiple organ damage, including kidney damage. However, the underlying mechanism remains unknown. The purpose of our study was to explore the effect of tubule-specific C5b-9 deposition induced by TCE sensitization on renal tubular ferroptosis and its mechanism. By analyzing pathological changes of TCE-sensitization-mice kidney, we observed a significant renal tubular ferroptosis, which was alleviated by CD59, a C5b-9 inhibitory protein. Moreover, this phenomenon was also replicated in a C5b-9-attacked HK-2 cell model. Further experiments identified that C5b-9 induced cytosolic Ca2+ overload in renal tubular epithelia cells from TCE-sensitization-mice and HK-2 cells. Furthermore, in vitro experiments showed that BAPTA-AM, an intracellular Ca2+ chelator, could rescued ferroptosis induced by C5b-9 in HK-2 cells. Taken together, TCE sensitization induced renal tubular ferroptosis is mediated by C5b-9 and cytosolic Ca2+ overload may play a key role.

Thrombotic Microangiopathy, Podocytopathy, and Damage to the Renal Tubules with Severe Proteinuria and Acute Renal Dysfunction Induced by Lenvatinib.

Lenvatinib, a tyrosine kinase inhibitor (TKI), is a stronger inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptors 1 to 4, and platelet-derived growth factor receptor (PDGFR) than other TKIs. We herein report a 77-year-old Japanese woman who received the minimum dose of lenvatinib for treatment of hepatocellular carcinoma. Within one month of starting treatment, she developed severe proteinuria, hypertension, and renal dysfunction. A kidney biopsy showed drug-induced thrombotic microangiopathy, podocytopathy, and polar vasculosis. We also observed damage to the renal tubules, where PDGFR is located. To our knowledge, this is the first report of lenvatinib-induced damage to the renal tubules.

Differential lipidomics of HK-2 cells and exosomes under high glucose stimulation.

Abnormal cellular lipid metabolism has a very important role in the occurrence and progression of diabetic kidney disease (DKD). However, the lipid composition and differential expression by high glucose stimulation of renal tubular cells and their exosomes, which is a vital part of the development of DKD, are largely unknown. In this study, based on targeted lipid analysis by isotope labeling and tandem mass spectrometry, a total of 421 and 218 lipid species were quantified in HK-2 cells and exosomes, respectively. More importantly, results showed that GM3 d18:1/22:0, GM3 d18:1/16:0, GM3 d18:0/16:0, GM3 d18:1/22:1 were significantly increased, while LPE18:1, LPE, CL66:4 (16:1), BMP36:3, CL70:7 (16:1), CL74:8 (16:1) were significantly decreased in high glucose-stimulated HK-2 cells. Also, PG36:1, FFA22:5, PC38:3, SM d18:1/16:1, CE-16:1, CE-18:3, CE-20:5, and CE-22:6 were significantly increased, while GM3 d18:1/24:1, GM3 were significantly decreased in exosomes secreted by high glucose-stimulated HK-2 cells. Furthermore, TAG, PC, CL were decreased significantly in the exosomes comparing with the HK-2 cells, and LPA18:2, LPI22:5, PG32:2, FFA16:1, GM3 d18:1/18:1, GM3 d18:1/20:1, GM3 d18:0/20:0, PC40:6p, TAG52:1(18:1), TAG52:0(18:0), CE-20:5, CE-20:4, CE-22:6 were only found in exosomes. In addition, the expression of PI4P in HK-2 cells decreased under a high glucose state. These data may be useful to provide new targets for exploring the mechanisms of DKD.

SGLT2 inhibitors in the treatment of type 2 cardiorenal syndrome: Focus on renal tubules.

The pathogenesis of type 2 cardiorenal syndrome (CRS) is mostly associated with reduced cardiac output, increased central venous pressure (CVP), activation of the renin-angiotensin-aldosterone system (RAAS), inflammation, and oxidative stress. As a drug to treat diabetes, sodium-glucose transporter 2 inhibitor (SGLT2i) has been gradually found to have a protective effect on the heart and kidney and has a certain therapeutic effect on CRS. In the process of chronic heart failure (CHF) leading to chronic renal insufficiency, the renal tubular system, as the main functional part of the kidney, is the first to be damaged, but this damage can be reversed. In this review, we focus on the protective mechanisms of SGLT2i targeting renal tubular in the treatment of CRS, including natriuresis and diuresis to relieve renal congestion, attenuate renal tubular fibrosis, improve energy metabolism of renal tubular, and slow tubular inflammation and oxidative stress. This may have beneficial effects on the treatment of CRS and is a direction for future research.

A Novel Renoprotective Strategy: Upregulation of PD-L1 Mitigates Cisplatin-Induced Acute Kidney Injury.

The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, with the classical markers elevated, consistent with the response to cisplatin treatment. Through assessments of the components of the immune system, both locally and globally, we demonstrate that the immune microenvironment of injured kidneys was associated with an increased infiltration of CD4+ T cells and macrophages concomitant with decreased Treg cell populations. Our cell-based assays and animal studies further show that cisplatin exposure downregulated the protein levels of programmed death-ligand 1 (PD-L1), an immune checkpoint protein, in primary renal proximal tubular epithelial cells, and that these inhibitions were dose-dependent. After orthotopic delivery of PD-L1 gene into the kidneys, cisplatin-exposed mice displayed lower levels of both serum urea nitrogen and creatinine upon PD-L1 expression. Our data suggest a renoprotective effect of the immune checkpoint protein, and thereby provide a novel therapeutic strategy for cisplatin-induced AKI.

Effects of intrauterine growth restriction during late pregnancy on the ovine fetal renal function and antioxidant capacity.

This study investigated the effects of intrauterine growth restriction during late pregnancy on the ovine fetal renal function and renal antioxidant capacity. Eighteen ewes pregnant were randomly divided into control group (CG, ad libitum, 0.67 MJ ME·BW-0.75 ·day-1 , n = 6), restricted group 1 (RG1, 0.18 MJ ME·BW-0.75 ·day-1 , n = 6), and restricted group 2 (RG2, 0.33 MJ ME·BW-0.75 ·day-1 , n = 6). At 140 days, the fetal blood, allantoic fluid and kidney tissue were collected to determinate fetal renal function and renal antioxidant capacity. The results showed that the fetal weight, kidney weight, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), aquaporin-2 (AQP-2) and aquaporin-3 (AQP-3), and total antioxidant capacity (T-AOC) in RG1 group were decreased compared with the CG (P < 0.05), but the contents of ß2-Microglobulin (ß 2-MG), cystatin C (Cys-C), filtered sodium excretion fraction (FENa), malondialdehyde (MDA), and hydroxyl radical (OH) in RG1 group were increased (P < 0.05). The impaired ovine fetal renal growth, antioxidant imbalance and dysfunction of glomerulus ultrafiltration, and the renal tubules reabsorption were induced by maternal malnutrition during late pregnancy.