Optimizing coronary CT angiography quality with motion-compensated reconstruction for second-generation dual-layer spectral detector CT.

OBJECTIVES: To investigate the effect of motion-compensated reconstruction (MCR) algorithm on improving the image quality of coronary computed tomography angiography (CCTA) using second-generation dual-layer spectral detector computed tomography (DLCT), and to evaluate the influence of heart rate (HR) on the motion-correction efficacy of this algorithm. MATERIALS AND METHODS: We retrospectively enrolled 127 patients who underwent CCTA for suspected coronary artery disease using second-generation DLCT. We divided the patients into two subgroups according to their average HR during scanning: the "HR < 75 bpm" group and the "HR ≥ 75 bpm" group. All images were reconstructed by the standard (STD) algorithm and MCR algorithm. Subjective image quality (4-point Likert scale), interpretability, and objective image quality between the STD and MCR in the whole population and within each subgroup were compared. RESULTS: MCR showed significantly higher Likert scores and interpretability than STD on the per-segment (3.58 ± 0.69 vs. 2.82 ± 0.93, 98.4% vs. 91.9%), per-vessel (3.12 ± 0.81 vs. 2.12 ± 0.74, 96.3% vs. 78.7%) and per-patient (2.57 ± 0.76 vs. 1.62 ± 0.55, 90.6% vs. 59.1%) levels (all p < 0.001). In the analysis of HR subgroups on a per-vessel basis of interpretability, significant differences were observed only in the right coronary artery in the low HR group, whereas significant differences were noted in three major coronary arteries in the high HR group. For objective image quality assessment, MCR significantly improved the SNR (13.22 ± 4.06 vs. 12.72 ± 4.06) and the contrast-to-noise ratio (15.84 ± 4.82 vs. 15.39 ± 4.38) compared to STD (both p < 0.001). CONCLUSION: MCR significantly improves the subjective image quality, interpretability, and objective image quality of CCTA, especially in patients with higher HRs. CLINICAL RELEVANCE STATEMENT: The motion-compensated reconstruction algorithm of the second-generation dual-layer spectral detector computed tomography is helpful in improving the image quality of coronary computed tomography angiography in clinical practice, especially in patients with higher heart rates. KEY POINTS: Motion artifacts from cardiac movement affect the quality and interpretability of coronary computed tomography angiography (CCTA). This motion-compensated reconstruction (MCR) algorithm significantly improves the image quality of CCTA in clinical practice. Image quality improvement by using MCR was more significant in the high heart rate group.

Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progression.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other than DNMT3A (non- DNMT3A CHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes. Methods: In this study, we examined the prospective associations between CHIP and CKD progression events in four cohorts of CKD patients (total N = 5,772). The primary outcome was a composite of 50% kidney function decline or kidney failure. The slope of eGFR decline was examined as a secondary outcome. Mendelian randomization techniques were then used to investigate potential causal effects of CHIP on eGFR decline. Finally, kidney function was assessed in adenine-fed CKD model mice having received a bone marrow transplant recapitulating Tet2 -CHIP compared to controls transplanted wild-type bone marrow. Results: Across all cohorts, the average age was 66.4 years, the average baseline eGFR was 42.6 ml/min/1.73m 2 , and 24% had CHIP. Upon meta-analysis, non- DNMT3A CHIP was associated with a 59% higher relative risk of incident CKD progression (HR 1.59, 95% CI: 1.02-2.47). This association was more pronounced among individuals with diabetes (HR 1.29, 95% CI: 1.03-1.62) and with baseline eGFR ≥ 30 ml/min/1.73m (HR 1.80, 95% CI: 1.11-2.90). Additionally, the annualized slope of eGFR decline was steeper among non- DNMT3A CHIP carriers, relative to non-carriers (ß -0.61 ± 0.31 ml/min/1.73m 2 , p = 0.04). Mendelian randomization analyses suggested a causal role for CHIP in eGFR decline among individuals with diabetes. In a dietary adenine mouse model of CKD, Tet2 -CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis. Conclusion: Non- DNMT3A CHIP is a potentially targetable novel risk factor for CKD progression.

Preparation and Properties of Polyaniline/Hydroxypropyl Methylcellulose Composite Conductive Thin Films.

In this work, a chemical grafting polymerization method was employed to synthesize EHPMC-g-PANI self-supporting films. Polyaniline (PANI) was grafted onto hydroxypropyl methylcellulose (HPMC) modified with epichlorohydrin (EPHMC) to obtain an EHPMC-g-PANI aqueous dispersion, which was subsequently dried to form the self-supporting films. The introduction of HPMC, with its excellent film-forming ability and mechanical strength, successfully addressed the poor film-forming ability and mechanical properties intrinsic to PANI. Compared to in situ polymerized HPMC/PANI, the EHPMC-g-PANI exhibited significantly improved storage stability. Moreover, the fabricated EHPMC-g-PANI films displayed a more uniform and smoother morphology. The conductivity of all the films ranged from 10-2 to 10-1 S/cm, and their tensile strength reached up to 36.1 MPa. These results demonstrate that the prepared EHPMC-g-PANI holds promising potential for applications in various fields, including conductive paper, sensors, and conductive inks.

Predicting Left Ventricular Adverse Remodeling After Transcatheter Aortic Valve Replacement: A Radiomics Approach.

RATIONALE AND OBJECTIVES: To develop a radiomics model based on cardiac computed tomography (CT) for predicting left ventricular adverse remodeling (LVAR) in patients with severe aortic stenosis (AS) who underwent transcatheter aortic valve replacement (TAVR). MATERIALS AND METHODS: Patients with severe AS who underwent TAVR from January 2019 to December 2022 were recruited. The cohort was divided into adverse remodeling group and non-adverse remodeling group based on LVAR occurrence, and further randomly divided into a training set and a validation set at an 8:2 ratio. Left ventricular radiomics features were extracted from cardiac CT. The least absolute shrinkage and selection operator regression was utilized to select the most relevant radiomics features and clinical features. The radiomics features were used to construct the Radscore, which was then combined with the selected clinical features to build a nomogram. The predictive performance of the models was evaluated using the area under the curve (AUC), while the clinical value of the models was assessed using calibration curves and decision curve analysis. RESULTS: A total of 273 patients were finally enrolled, including 71 with adverse remodeling and 202 with non-adverse remodeling. 12 radiomics features and five clinical features were extracted to construct the radiomics model, clinical model, and nomogram, respectively. The radiomics model outperformed the clinical model (training AUC: 0.799 vs. 0.760; validation AUC: 0.766 vs. 0.755). The nomogram showed highest accuracy (training AUC: 0.859, validation AUC: 0.837) and was deemed most clinically valuable by decision curve analysis. CONCLUSION: The cardiac CT-based radiomics features could predict LVAR after TAVR in patients with severe AS.

Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI. In three population-based epidemiology cohorts, we found that CHIP was associated with a greater risk of incident AKI, which was more pronounced in patients with AKI requiring dialysis and in individuals with somatic mutations in genes other than DNMT3A, including mutations in TET2 and JAK2. Mendelian randomization analyses supported a causal role for CHIP in promoting AKI. Non-DNMT3A-CHIP was also associated with a nonresolving pattern of injury in patients with AKI. To gain mechanistic insight, we evaluated the role of Tet2-CHIP and Jak2V617F-CHIP in two mouse models of AKI. In both models, CHIP was associated with more severe AKI, greater renal proinflammatory macrophage infiltration and greater post-AKI kidney fibrosis. In summary, this work establishes CHIP as a genetic mechanism conferring impaired kidney function recovery after AKI via an aberrant inflammatory response mediated by renal macrophages.

Myocardial tissue remodeling in early adult obesity and its association with regional adipose tissue distribution and ectopic fat deposits: a prospective study.

OBJECTIVES: To evaluate the left ventricular (LV) myocardial tissue characteristics in early adult obesity and its association with regional adipose tissue and ectopic fat deposition. METHODS: Forty-nine obese adults (mean body mass index: 29.9 ± 2.0 kg/m2) and 44 healthy controls were prospectively studied. LV native and post-contrast T1 values, extracellular volume fraction (ECV), regional adipose tissue (epicardial, visceral, and subcutaneous adipose tissue (EAT, VAT, and SAT)), and ectopic fat deposition (hepatic and pancreatic proton density fat fractions (H-PDFF and P-PDFF)) based on magnetic resonance imaging were compared. The association was assessed by multivariable linear regression. RESULTS: The obese participants showed reduced global ECV compared to the healthy controls (p < 0.05), but there was no significant difference in global native or post-contrast T1 values between the two groups. Additionally, the obese individuals exhibited higher EAT, VAT, SAT, H-PDFF, and P-PDFF than the controls (p < 0.05). ECV was associated with insulin resistance, dyslipidemia, and systolic blood pressure (SBP) (p < 0.05). Multiple linear regression demonstrated that H-PDFF and SAT were independently associated with ECV in entire population (ß = - 0.123 and - 0.012; p < 0.05). CONCLUSIONS: Reduced myocardial ECV in patients with mild-to-moderate obesity and its relationship to SBP may indicate that cardiomyocyte hypertrophy, rather than extracellular matrix expansion, is primarily responsible for myocardial tissue remodeling in early adult obesity. Our findings further imply that H-PDFF and SAT are linked with LV myocardial tissue remodeling in this cohort beyond the growth difference and cardiovascular risk factors. CLINICAL TRIALS REGISTRATION: Effect of lifestyle intervention on metabolism of obese patients based on smart phone software (ChiCTR1900026476). CLINICAL RELEVANCE STATEMENT: Myocardial fibrosis in severe obesity predicts poor prognosis. We showed that cardiomyocyte hypertrophy, not myocardial fibrosis, is the main myocardial tissue characteristic of early obesity. This finding raises the possibility that medical interventions, like weight loss, may prevent cardiac fibrosis. KEY POINTS: • Myocardial tissue characteristics in early adult obesity are unclear. • Myocardial extracellular volume fraction (ECV) can be quantitatively evaluated using T1 mapping based on cardiac magnetic resonance imaging (MRI). • Cardiac MRI-derived ECV may noninvasively evaluate myocardial tissue remodeling in early adult obesity.

Epidermal growth factor receptor activation is essential for kidney fibrosis development.

Fibrosis is the progressive accumulation of excess extracellular matrix and can cause organ failure. Fibrosis can affect nearly every organ including kidney and there is no specific treatment currently. Although Epidermal Growth Factor Receptor (EGFR) signaling pathway has been implicated in development of kidney fibrosis, underlying mechanisms by which EGFR itself mediates kidney fibrosis have not been elucidated. We find that EGFR expression increases in interstitial myofibroblasts in human and mouse fibrotic kidneys. Selective EGFR deletion in the fibroblast/pericyte population inhibits interstitial fibrosis in response to unilateral ureteral obstruction, ischemia or nephrotoxins. In vivo and in vitro studies and single-nucleus RNA sequencing analysis demonstrate that EGFR activation does not induce myofibroblast transformation but is necessary for the initial pericyte/fibroblast migration and proliferation prior to subsequent myofibroblast transformation by TGF-ß or other profibrotic factors. These findings may also provide insight into development of fibrosis in other organs and in other conditions.

Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as DNMT3A, TET2, ASXL1 and JAK2 and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than DNMT3A (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non-DNMT3A CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of Tet2-CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in Tet2-CHIP mice. Kidney macrophage infiltration was markedly increased in Tet2-CHIP mice and Tet2-CHIP mutant renal macrophages displayed greater proinflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.

EGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance.

Obesity and obesity-related health complications are increasing in prevalence. Adipose tissue from obese subjects has low-grade, chronic inflammation, leading to insulin resistance. Adipose tissue macrophages (ATMs) are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. In response to a high fat diet (HFD), ATM numbers initially increase by proliferation of resident macrophages, but subsequent increases also result from infiltration in response to chemotactic signals from inflamed adipose tissue. To elucidate the underlying mechanisms regulating the increases in ATMs and their proinflammatory phenotype, we investigated the role of activation of ATM epidermal growth factor receptor (EGFR). A high fat diet increased expression of EGFR and its ligand amphiregulin in ATMs. Selective deletion of EGFR in ATMs inhibited both resident ATM proliferation and monocyte infiltration into adipose tissue and decreased obesity and development of insulin resistance. Therefore, ATM EGFR activation plays an important role in adipose tissue dysfunction.

Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice.

Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in obesity leads to a state of low-grade chronic inflammation and dysregulated metabolism, resulting in insulin resistance and metabolic syndrome. Adipose tissue macrophages (ATMs) accumulate in obesity and are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. Macrophages are rich sources of cyclooxygenase (COX), the rate limiting enzyme for prostaglandin E2 (PGE2) production. When mice were fed a high-fat diet (HFD), ATMs increased expression of COX-2. Selective myeloid cell COX-2 deletion resulted in increased monocyte recruitment and proliferation of ATMs, leading to increased proinflammatory ATMs with decreased phagocytic ability. There were increased weight gain and adiposity, decreased peripheral insulin sensitivity and glucose utilization, increased adipose tissue inflammation and fibrosis, and abnormal adipose tissue angiogenesis. HFD pair-feeding led to similar increases in body weight, but mice with selective myeloid cell COX-2 still exhibited decreased peripheral insulin sensitivity and glucose utilization. Selective myeloid deletion of the macrophage PGE2 receptor subtype, EP4, produced a similar phenotype, and a selective EP4 agonist ameliorated the metabolic abnormalities seen with ATM COX-2 deletion. Therefore, these studies demonstrated that an ATM COX-2/PGE2/EP4 axis plays an important role in inhibiting adipose tissue dysfunction.

Myeloid cyclooxygenase-2/prostaglandin E2/E-type prostanoid receptor 4 promotes transcription factor MafB-dependent inflammatory resolution in acute kidney injury.

Following acute injury to the kidney, macrophages play an important role in recovery of functional and structural integrity, but organ fibrosis and progressive functional decline occur with incomplete recovery. Pro-resolving macrophages are characterized by increased cyclooxygenase 2 (COX-2) expression and this expression was selectively increased in kidney macrophages following injury and myeloid-specific COX-2 deletion inhibited recovery. Deletion of the myeloid prostaglandin E2 (PGE2) receptor, E-type prostanoid receptor 4 (EP4), mimicked effects seen with myeloid COX-2-/- deletion. PGE2-mediated EP4 activation induced expression of the transcription factor MafB in kidney macrophages, which upregulated anti-inflammatory genes and suppressed pro-inflammatory genes. Myeloid Mafb deletion recapitulated the effects seen with either myeloid COX-2 or EP4 deletion following acute kidney injury, with delayed recovery, persistent presence of pro-inflammatory kidney macrophages, and increased kidney fibrosis. Thus, our studies identified a previously unknown mechanism by which prostaglandins modulate macrophage phenotype following acute organ injury and provide new insight into mechanisms underlying detrimental kidney effects of non-steroidal anti-inflammatory drugs that inhibit cyclooxygenase activity.

Profile of Podocyte Translatome During Development of Type 2 and Type 1 Diabetic Nephropathy Using Podocyte-Specific TRAP mRNA RNA-seq.

Podocyte injury is important in development of diabetic nephropathy (DN). Although several studies have reported single-cell-based RNA sequencing (RNA-seq) of podocytes in type 1 DN (T1DN), the podocyte translating mRNA profile in type 2 DN (T2DN) has not previously been compared with that of T1DN. We analyzed the podocyte translatome in T2DN in podocin-Cre; Rosa26fsTRAP; eNOS-/-; db/db mice and compared it with that of streptozotocin-induced T1DN in podocin-Cre; Rosa26fsTRAP; eNOS-/- mice using translating ribosome affinity purification (TRAP) and RNA-seq. More than 125 genes were highly enriched in the podocyte ribosome. More podocyte TRAP genes were differentially expressed in T2DN than in T1DN. TGF-ß signaling pathway genes were upregulated, while MAPK pathway genes were downregulated only in T2DN, while ATP binding and cAMP-mediated signaling genes were downregulated only in T1DN. Genes regulating actin filament organization and apoptosis increased, while genes regulating VEGFR signaling and glomerular basement membrane components decreased in both type 1 and type 2 diabetic podocytes. A number of diabetes-induced genes not previously linked to podocyte injury were confirmed in both mouse and human DN. On the basis of differences and similarities in the podocyte translatome in T2DN and T1DN, investigators can identify factors underlying the pathophysiology of DN and novel therapeutic targets to treat diabetes-induced podocyte injury.

Deletion of Myeloid Interferon Regulatory Factor 4 (Irf4) in Mouse Model Protects against Kidney Fibrosis after Ischemic Injury by Decreased Macrophage Recruitment and Activation.

BACKGROUND: AKI is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery leads to chronic kidney injury. Previous studies by us and others have indicated that macrophage infiltration and polarization play key roles in recovery from AKI. The role in AKI recovery played by IFN regulatory factor 4 (IRF4), a mediator of polarization of macrophages to the M2 phenotype, is unclear. METHODS: We used mice with myeloid or macrophage cell-specific deletion of Irf4 (MΦ Irf4-/- ) to evaluate Irf4's role in renal macrophage polarization and development of fibrosis after severe AKI. RESULTS: Surprisingly, although macrophage Irf4 deletion had a minimal effect on early renal functional recovery from AKI, it resulted in decreased renal fibrosis 4 weeks after severe AKI, in association with less-activated macrophages. Macrophage Irf4 deletion also protected against renal fibrosis in unilateral ureteral obstruction. Bone marrow-derived monocytes (BMDMs) from MΦ Irf4-/- mice had diminished chemotactic responses to macrophage chemoattractants, with decreased activation of AKT and PI3 kinase and increased PTEN expression. PI3K and AKT inhibitors markedly decreased chemotaxis in wild-type BMDMs, and in a cultured macrophage cell line. There was significant inhibition of homing of labeled Irf4-/- BMDMs to postischemic kidneys. Renal macrophage infiltration in response to AKI was markedly decreased in MΦ Irf4-/- mice or in wild-type mice with inhibition of AKT activity. CONCLUSIONS: Deletion of Irf4 from myeloid cells protected against development of tubulointerstitial fibrosis after severe ischemic renal injury in mice, due primarily to inhibition of AKT-mediated monocyte recruitment to the injured kidney and reduced activation and subsequent polarization into a profibrotic M2 phenotype.

Podocyte EGFR Inhibits Autophagy Through Upregulation of Rubicon in Type 2 Diabetic Nephropathy.

Renal epidermal growth factor receptor (EGFR) signaling is activated in models of diabetic nephropathy (DN), and inhibition of the EGFR signaling pathway protects against the development of DN. We have now determined that in cultured podocytes, high glucose led to increases in activation of EGFR signaling but decreases in autophagy activity as indicated by decreased beclin-1 and inhibition of LC3B autophagosome formation as well as increased rubicon (an autophagy inhibitor) and SQSTM1 (autophagy substrate). Either genetic (small interfering [si]EGFR) or pharmacologic (AG1478) inhibition of EGFR signaling attenuated the decreased autophagy activity. In addition, rubicon siRNA knockdown prevented high glucose-induced inhibition of autophagy in podocytes. We further examined whether selective EGFR deletion in podocytes affected the progression of DN in type 2 diabetes. Selective podocyte EGFR deletion had no effect on body weight or fasting blood sugars in either db/db mice or nos3 -/-; db/db mice, a model of accelerated type 2 DN. However selective podocyte EGFR deletion led to relative podocyte preservation and marked reduction in albuminuria and glomerulosclerosis, renal proinflammatory cytokine/chemokine expression, and decreased profibrotic and fibrotic components in nos3 -/-; db/db mice. Podocyte EGFR deletion led to decreased podocyte expression of rubicon, in association with increased podocyte autophagy activity. Therefore, activation of EGFR signaling in podocytes contributes to progression of DN at least in part by increasing rubicon expression, leading to subsequent autophagy inhibition and podocyte injury.

Serum Lipid Metabolic Derangement is Associated with Disease Progression During Chronic HBV Infection.

BACKGROUND: To investigate the relationship between serum lipid levels and disease progression during chronic hepatitis B virus infection. METHODS: We selected 73 healthy controls and 163 patients with chronic HBV infection as the study subjects. The chronic HBV infection patients were divided into the HBV carrier group (74 patients), chronic hepatitis B group (71 patients), and liver cirrhosis group (21 patients). The age, gender, body mass index, blood lipid index, liver function index, and HBV DNA levels of all participants were tested and recorded. A t-test or the Mann-Whitney U test was used to compare the data between two groups; data from multiple groups were compared using one-way ANOVA or the Kruskal-Wallis Test. RESULTS: We observed that the serum HDL cholesterol (1.00 ± 0.30 mmol/L in the HBV-infected group, 1.29 ± 0.23 mmol/L in the control group) and APOA (1.29 ± 0.35 mmol/L, 1.36 ± 0.21 mmol/L, respectively) concentrations were significantly lower in the HBV-infected group than in the control group (p < 0.05). As the disease progressed, the blood lipid and lipoprotein values were significantly lower in the cirrhosis group TC (3.26 ± 1.00 mmol/L), HDL cholesterol (0.77 ± 0.33 mmol/L), LDL cholesterol (2.09 ± 0.62 mmol/L), and APOB (0.57 ± 0.18 mmol/L) compared with the control group, the carrier group, and the chronic hepatitis B group (p < 0.05). The serum HBV DNA level was significantly, positively correlated with the blood HDL concentration (carrier group R = 0.340, p = 0.02; chronic hepatitis B group R = 0.329, p = 0.014). There was no correlation between the HBV DNA and lipid levels in patients with cirrhosis. CONCLUSIONS: Serum lipid metabolic derangement was associated with disease progression during chronic HBV infection. Liver function and blood lipid levels were significantly lower in patients with hepatitis B-related cirrhosis.

The Role of the EGF Receptor in Sex Differences in Kidney Injury.

BACKGROUND: Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury. METHODS: To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines. RESULTS: In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells. CONCLUSIONS: These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.

TGF-ß promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration.

TGF-ß signals through a receptor complex composed of 2 type I and 2 type II (TGF-ßRII) subunits. We investigated the role of macrophage TGF-ß signaling in fibrosis after AKI in mice with selective monocyte/macrophage TGF-ßRII deletion (macrophage TGF-ßRII-/- mice). Four weeks after injury, renal TGF-ß1 expression and fibrosis were higher in WT mice than macrophage TGF-ßRII-/- mice, which had decreased renal macrophages. The in vitro chemotactic response to f-Met-Leu-Phe was comparable between bone marrow-derived monocytes (BMMs) from WT and macrophage TGF-ßRII-/- mice, but TGF-ßRII-/- BMMs did not respond to TGF-ß. We then implanted Matrigel plugs suffused with either f-Met-Leu-Phe or TGF-ß1 into WT or macrophage TGF-ßRII-/- mice. After 6 days, f-Met-Leu-Phe induced similar macrophage infiltration into the Matrigel plugs of WT and macrophage TGF-ßRII-/- mice, but TGF-ß induced infiltration only in WT mice. We further determined the number of labeled WT or TGF-ßRII-/- BMMs infiltrating into WT kidneys 20 days after ischemic injury. There were more labeled WT BMMs than TGF-ßRII-/- BMMs. Therefore, macrophage TGF-ßRII deletion protects against the development of tubulointerstitial fibrosis following severe ischemic renal injury. Chemoattraction of macrophages to the injured kidney through a TGF-ß/TGF-ßRII axis is a heretofore undescribed mechanism by which TGF-ß can mediate renal fibrosis during progressive renal injury.

Renal Medullary Interstitial COX-2 (Cyclooxygenase-2) Is Essential in Preventing Salt-Sensitive Hypertension and Maintaining Renal Inner Medulla/Papilla Structural Integrity.

COX (cyclooxygenase)-derived prostaglandins regulate renal hemodynamics and salt and water homeostasis. Inhibition of COX activity causes blood pressure elevation. In addition, chronic analgesic abuse can induce renal injury, including papillary necrosis. COX-2 is highly expressed in the kidney papilla in renal medullary interstitial cells (RMICs). However, its role in blood pressure and papillary integrity in vivo has not been definitively studied. In mice with selective, inducible RMIC COX-2 deletion, a high-salt diet led to an increase in blood pressure that peaked at 4 to 5 weeks and was associated with increased papillary expression of AQP2 (aquaporin 2) and ENac (epithelial sodium channel) and decreased expression of cystic fibrosis transmembrane conductance regulator. With continued high-salt feeding, the mice with RMIC COX-2 deletion had progressive decreases in blood pressure from its peak. After return to a normal-salt diet for 3 weeks, blood pressure remained low and was associated with a persistent urinary concentrating defect. Within 2 weeks of institution of a high-salt diet, increased apoptotic RMICs and collecting duct cells could be detected in papillae with RMIC deletion of COX-2, and by 9 weeks of high salt, there was a striking loss of the papillae. Therefore, RMIC COX-2 expression plays a crucial role in renal handling water and sodium homeostasis, preventing salt-sensitive hypertension and maintaining structural integrity of papilla.