Use of Janus kinase inhibitors in dermatomyositis: a systematic literature review.

Dermatomyositis (DM) is an idiopathic inflammatory myopathy that commonly manifests with proximal muscle weakness and is associated with extramuscular pathology, including characteristic skin lesions such as Gottron's papules and heliotrope rash, as well as lung, gastrointestinal, joint, and cardiac involvement. Systemic corticosteroids are a cornerstone of therapy, and more recently intravenous immunoglobulin (IVIG; OCTAGAM®) has been approved by the US Food and Drug Administration for the treatment of adults with DM. Both steroids and IVIG represent nonspecific anti-inflammatory therapy, and more targeted approaches are lacking. Transcriptomics has identified upregulation of interferon (IFN)-regulated genes as key features of both adult DM and juvenile DM (JDM). Accordingly, blocking IFN signalling through inhibition of the Janus kinase (JAK) pathway represents a potential treatment option for DM. Placebo-controlled trial data assessing the use of JAK inhibitors for the treatment of DM are limited; as such, a systematic literature review was undertaken to assess the evidence of JAK inhibitors in the treatment of patients with DM. Terms related to DM and JAK inhibitors were searched using PubMed, Embase, Web of Science, Scopus, and Dimensions to identify peer-reviewed publications reporting patients with DM who were treated with a JAK inhibitor. Baseline demographics, clinical characteristics, and treatment outcome data were extracted. A total of 48 publications reporting 145 unique patients (adult DM, n=84; JDM, n=61) were identified. Among cases of adult DM, 61 of 84 (73%) had refractory skin disease at baseline, and all (61 of 61) reported improvement in cutaneous symptoms. Of patients with adult DM, 16 of 84 (19%) had refractory muscle disease at baseline, and all (16 of 16) reported improvement in muscle symptoms. In patients with adult DM complicated by interstitial lung disease (ILD; n=33), 31 (94%) patients improved with JAK inhibitor treatment. Among cases of JDM with refractory skin disease at baseline (60 of 61), most patients (57 of 60; 95%) showed improvements in skin symptoms after JAK inhibitor treatment. Of patients with JDM with refractory muscle disease at baseline (36 of 61), most (30 of 36; 83%) reported improvement in muscle symptoms. Four patients with JDM and ILD experienced improvement in lung disease activity following treatment with a JAK inhibitor. Among both DM and JDM cases, all patients (17 with DM and 16 with JDM) who had elevated serum IFN and/or IFN-stimulated gene expression at baseline showed reduction in IFN or IFN gene expression. Although the conclusions that can be drawn from this analysis are limited because of the differences in assessments used across publications, overall treatment of patients with DM or JDM with a JAK inhibitor was associated with significant improvement of a wide range of DM manifestations, including skin lesions, muscle weakness, and ILD. Our systematic literature review suggests that JAK inhibitors may be a viable treatment option for DM/JDM, and randomised controlled trials are necessary to confirm these findings.

The association of triglyceride levels with the incidence of initial and recurrent acute pancreatitis.

BACKGROUND: This retrospective cohort study assessed the annualized incidence rate (IR) of acute pancreatitis (AP) in a nationally representative US adult population, as well as the variation in the risk of AP events across strata of triglyceride (TG) levels. METHODS: Data were obtained from IQVIA's US Ambulatory Electronic Medical Records (EMR) database linked with its LRxDx Open Claims database. Inclusion criteria included ≥1 serum TG value during the overlapping study period of the EMR and claims databases, ≥1 claim in the 12-month baseline period, and ≥ 1 claim in the 12 months post index. All TG measurements were assigned to the highest category reached: < 2.26, ≥2.26 to ≤5.65, > 5.65 to ≤9.94, > 9.94, and > 11.29 mmol/L (< 200, ≥200 to ≤500, > 500 to ≤880, > 880, and > 1000 mg/dL, respectively). The outcome of interest was AP, defined as a hospitalization event with AP as the principal diagnosis. RESULTS: In total, 7,119,195 patients met the inclusion/exclusion criteria, of whom 4158 (0.058%) had ≥1 AP events in the prior 12 months. Most patients (83%) had TGs < 2.26 mmol/L (< 200 mg/dL), while < 1% had TGs > 9.94 mmol/L (> 880 mg/dL). Overall, the IR of AP was low (0.08%; 95% confidence internal [CI], 0.08-0.08%), but increased with increasing TGs (0.08% in TGs < 2.26 mmol/L [< 200 mg/dL] to 1.21% in TGs > 11.29 mmol/L [> 1000 mg/dL]). In patients with a prior history of AP, the IR of AP increased dramatically; patients with ≥2 AP events at baseline had an IR of 29.98% (95% CI, 25.1-34.9%). CONCLUSION: The risk of AP increases with increasing TG strata; however, the risk increases dramatically among patients with a recent history of AP.

Serum stimulation of CCR7 chemotaxis due to coagulation factor XIIa-dependent production of high-molecular-weight kininogen domain 5.

Chemokines and their receptors play a critical role in immune function by directing cell-specific movement. C-C chemokine receptor 7 (CCR7) facilitates entry of T cells into lymph nodes. CCR7-dependent chemotaxis requires either of the cognate ligands C-C chemokine ligand 19 (CCL19) or CCL21. Although CCR7-dependent chemotaxis can be augmented through receptor up-regulation or by increased chemokine concentrations, we found that chemotaxis is also markedly enhanced by serum in vitro. Upon purification, the serum cofactor activity was ascribed to domain 5 of high-molecular-weight kininogen. This peptide was necessary and sufficient for accelerated chemotaxis. The cofactor activity in serum was dependent on coagulation factor XIIa, a serine protease known to induce cleavage of high-molecular-weight kininogen (HK) at sites of inflammation. Within domain 5, we synthesized a 24-amino acid peptide that could recapitulate the activity of intact serum through a mechanism distinct from up-regulating CCR7 expression or promoting chemokine binding to CCR7. This peptide interacts with the extracellular matrix protein thrombospondin 4 (TSP4), and antibodies to TSP4 neutralize its activity. In vivo, an HK domain 5 peptide stimulated homing of both T and B cells to lymph nodes. A circulating cofactor that is activated at inflammatory foci to enhance lymphocyte chemotaxis represents a powerful mechanism coupling inflammation to adaptive immunity.

Vitamin D may not improve lipid levels: a serial clinical laboratory data study.

BACKGROUND: Vitamin D deficiency is highly prevalent and is associated with dyslipidemia and cardiovascular disease. The impact of correcting vitamin D deficiency on blood lipids, strong cardiovascular disease prognostic factors, is unknown. METHODS AND RESULTS: To determine relationships between 25-hydroxyvitamin D levels and lipids, we analyzed 4.06 million deidentified patient laboratory test results from September 2009 through February 2011. We performed a cross-sectional study of this population to determine associations between 25-hydroxyvitamin D levels and lipids across clinically defined strata. We also conducted a retrospective cohort study of vitamin D deficient patients to investigate how changes in 25-hydroxyvitamin D levels relate to changes in lipid levels. After exclusions, 107 811 patients with serial testing were selected for cross-sectional analysis. Compared with vitamin D deficient patients (<20 ng/mL), those with optimal levels (≥30 ng/mL) had lower mean total cholesterol (-1.9 mg/dL; 95% confidence interval [95% CI], -1.2 to -2.7; P<0.0001), lower low-density lipoprotein cholesterol (-5.2 mg/dL; 95% CI, -4.5 to -5.8; P<0.0001), higher high-density lipoprotein cholesterol (4.8 mg/dL; 95% CI, 4.5-5.0; P<0.0001), and lower triglycerides (-7.5 mg/dL; 95% CI, -6.2 to -8.7; P<0.0001). For the retrospective cohort analysis, raising vitamin D levels from <20 to ≥30 ng/mL (n=6260), compared with remaining at <20 ng/mL (n=2332), was associated with a mean increase in total cholesterol (0.77 mg/dL; 95% CI, 0.18-1.36; P=0.01) and high-density lipoprotein cholesterol (0.42 mg/dL; 95% CI, 0.08-0.76; P=0.02) but nonsignificant changes in low-density lipoprotein cholesterol (0.32 mg/dL; 95% CI, -0.01 to 0.66; P=0.06) and triglycerides (0.04 mg/dL; 95% CI, -2.16 to 2.23 mg/dL; P=0.97). CONCLUSIONS: Although vitamin D deficiency is associated with an unfavorable lipid profile in cross-sectional analyses, correcting for a deficiency might not translate into clinically meaningful changes in lipid concentrations; however, data from intervention trials are required to confirm these findings.

The short-term effects of vitamin D repletion on cholesterol: a randomized, placebo-controlled trial.

OBJECTIVE: Vitamin D deficiency is common and associated with dyslipidemia. However, it is unclear whether oral vitamin D supplementation improves the lipid profile. Therefore, we conducted a randomized, placebo-controlled trial to determine the short-term effects of vitamin D repletion on the lipid profile. METHODS AND RESULTS: One hundred fifty-one vitamin D-deficient (25-hydroxyvitamin D <20 ng/mL) adults with elevated risk for cardiovascular disease were randomized to receive either 50 000 IU of vitamin D3 weekly for 8 weeks or placebo. The primary outcome was the change in small low-density lipoprotein (LDL) particle number. Secondary outcomes included changes in other nuclear magnetic resonance-based and chemical lipid fractions. Vitamin D failed to improve the lipid profile. Compared with the placebo, vitamin D repletion did not change small LDL particle number (mean change, +18 nmol/L; 95% CI [-80 to +116 nmol/L]; P=0.63). There were also no changes in the chemical lipid profile: total cholesterol (+5.8 mg/dL, 95% CI [-1.4 to +13.0 mg/dL], P=0.14); LDL cholesterol (+3.8 mg/dL, 95% CI [-2.5 to +10.2 mg/dL], P=0.13); high-density lipoprotein cholesterol (+0.4 mg/dL 95% CI [-1.6 to +2.6 mg/dL], P=0.71); and triglycerides (+7.9 mg/dL 95% CI [-6.5 to +22.3 mg/dL]). In the vitamin D repletion group, exploratory multivariate regression analysis demonstrates that changes in LDL cholesterol were positively correlated with the changes in serum calcium (P<0.001) and inversely with the changes in serum parathyroid hormone (P=0.02). CONCLUSIONS: In contrast to the association between low 25-hydroxyvitamin D levels and dyslipidemia, correcting vitamin D deficiency in the short-term does not improve the lipid profile. Repletion of 25-hydroxyvitamin D levels raised serum calcium levels and decreased serum parathyroid hormone levels. These expected physiological responses to vitamin D therapy were correlated with a significant increase in LDL cholesterol. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01008384.

Vitamin D3 repletion in chronic kidney disease stage 3: effects on blood endotoxin activity, inflammatory cytokines, and intestinal permeability.

BACKGROUND: Vitamin D deficiency is common in the general population and even more prevalent in patients with chronic kidney disease (CKD). Low 25-hydroxyvitamin D [25(OH)D] levels have been associated with cardiovascular disease, though a definitive mechanistic link has not been established. Further, it is unclear if repleting vitamin D mitigates the excess risk observed in epidemiologic studies. Because vitamin D may regulate innate immunity and gut epithelial differentiation, we hypothesized that oral cholecalciferol (D3) would result in decreased blood endotoxin activity, a potential risk factor for cardiovascular disease. STUDY DESIGN, SETTING & PARTICIPANTS, INTERVENTION: We studied 12 stable outpatients with CKD stage 3 and 25(OH)D deficiency, who received D3 30,000 units weekly for 8 weeks. The primary endpoint was the change in blood endotoxin activity. RESULTS: Baseline endotoxin activity correlated with 25(OH)D levels (r = -0.60, p = 0.04). Endotoxin activity decreased by 25% from baseline (p = 0.03). Despite the decrease in endotoxin activity, there was no change in intestinal permeability. CONCLUSION: The results of this study suggest that vitamin D repletion therapy may have an effect on endotoxin activity in early CKD. Further intervention studies using vitamin D in the CKD population are required.

Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial.

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg-1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of -27.1% (37.4) (95% confidence interval -71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 .

Methylamine clearance by haemodialysis is low.

BACKGROUND: Dialysis adequacy is currently judged by measures of urea clearance. However, urea is relatively non-toxic and has properties distinct from large classes of other retained solutes. In particular, intracellularly sequestered solutes are likely to behave differently than urea. METHODS: We studied an example of this class, the aliphatic amine monomethylamine (MMA), in stable haemodialysis outpatients (n = 10) using an HPLC-based assay. RESULTS: Mean MMA levels pre-dialysis in end-stage renal disease subjects were 76 +/- 15 microg/L compared to 32 +/- 4 microg/L in normal subjects (n = 10) (P < 0.001). Mean urea reduction was 62% while the reduction ratio for MMA was 43% (P < 0.01). MMA levels rebounded in the 1 hour post-dialytic period to 85% of baseline, whereas urea levels rebounded only to 47% of baseline. MMA had a much larger calculated volume of distribution compared to urea, consistent with intracellular sequestration. Measures of intra-red blood cell (RBC) MMA concentrations confirmed greater levels in RBCs than in plasma with a ratio of 4.9:1. Because of the intracellular sequestration of MMA, we calculated its clearance using that amount removed from whole blood. Clearances for urea averaged 222 +/- 41 ml/min and for MMA 121 +/- 14 ml/min, while plasma clearance for creatinine was 162 +/- 20 ml/min (P < 0.01, for all differences). Using in vitro dialysis, in the absence of RBCs, solute clearance rates were similar: 333 +/- 6, 313 +/- 8 and 326 +/- 4 ml/min for urea, creatinine and MMA, respectively. These findings suggest that the lower MMA clearance relative to creatinine in vivo is a result of MMA movement into RBCs within the dialyser blood path diminishing its removal by dialysis. CONCLUSION: In conclusion, we find that, in conventional haemodialysis, MMA is not cleared as efficiently as urea or creatinine and raise the possibility that RBCs may limit its dialysis not merely by failing to discharge it, but by further sequestering it as blood passes through the dialyser.

Lipid metabolism in dialysis patients-the story gets more complicated.

Cardiovascular disease continues to be the foremost cause of morbidity and mortality in dialysis patients. Compared with the general population, dialysis patients suffer from an accelerated disease course that is, at least in part, resistant to conventional therapy. While there are a myriad of potential explanations for this resistance, derangements in lipid metabolism probably play an important role. Here, we discuss the significance of altered lipid metabolism in uremia, such as oxidative lipoprotein modification and the pathophysiology of adipose tissue; limitations of conventional approaches to dyslipidemia such as statin therapy and traditional lipid profiles; and areas of investigation with potential for new therapy, such as reverse cholesterol transport.

Quantifying Human Monocyte Chemotaxis In Vitro and Murine Lymphocyte Trafficking In Vivo.

Chemotaxis is migration along a specific chemical gradient1. Chemokines are chemotactic cytokines that promote cellular trafficking with anatomic and temporal specificity2. Chemotaxis is a critical function of lymphocytes and other immune cells that can be quantitatively assessed in vitro. This manuscript describes methods that permit the evaluation of chemotaxis, both in vitro and in vivo, for diverse cell types including cell lines and native cells. The in vitro, plate-based format permits the comparison of several conditions simultaneously in real-time, and can be completed within 1-4 h. In vitro assay conditions can be manipulated to introduce agonists and antagonists, as well as differentiate chemotaxis from chemokinesis, which is random movement. For in vivo trafficking assessments, immune cells can be labeled with multiple fluorescent dyes and used for adoptive transfer. The differential labeling of cells allows for mixed cell populations to be introduced into the same animal, thereby decreasing variance and reducing the number of animals required for an adequately powered experiment. Migration into lymphoid tissue occurs in as little as 1 h, and multiple tissue compartments can be sampled. Flow cytometry following tissue harvest allows for a rapid and quantitative analysis of the migratory patterns of multiple cell types.

A randomized clinical trial in vitamin D-deficient adults comparing replenishment with oral vitamin D3 with narrow-band UV type B light: effects on cholesterol and the transcriptional profiles of skin and blood.

Background: Vitamin D deficiency, defined as a serum 25-hydroxyvitamin D [25(OH)D] concentration <20 ng/mL, is correlated with a more atherogenic lipid profile. However, oral vitamin D supplementation does not lower LDL-cholesterol concentrations or raise HDL-cholesterol concentrations. This uncoupling between association and causation may result from a failure of oral vitamin D to mimic the effect of dermally synthesized vitamin D in response to ultraviolet type B (UVB) light.Objective: We tested the hypothesis that, in vitamin D-deficient adults, the replenishment of vitamin D with UVB exposure would lower LDL-cholesterol concentrations compared with the effect of oral vitamin D3 supplementation.Design: We performed a randomized clinical trial in vitamin D-deficient adults and compared vitamin D replenishment between subjects who received oral vitamin D3 (n = 60) and those who received narrow-band UVB exposure (n = 58) ≤6 mo.Results: There was no difference in the change from baseline LDL-cholesterol concentrations between oral vitamin D3 and UVB groups (difference in median of oral vitamin D3 minus that of UVB: 1.5 mg/dL; 95% CI: -5.0, 7.0 mg/dL). There were also no differences within groups or between groups for changes in total or HDL cholesterol or triglycerides. Transcriptional profiling of skin and blood, however, revealed significant upregulation of immune pathway signaling with oral vitamin D3 but significant downregulation with UVB.Conclusions: Correcting vitamin D deficiency with either oral vitamin D3 or UVB does not improve the lipid profile. Beyond cholesterol, these 2 modalities of raising 25(OH)D have disparate effects on gene transcription. This trial was registered at clinicaltrials.gov as NCT01688102.

Vitamin D-binding protein levels do not influence the effect of vitamin D repletion on serum PTH and calcium: data from a randomized, controlled trial.

CONTEXT: Vitamin D deficiency, defined by the total serum 25-hydroxyvitamin D [25(OH)D] level, is common and more prevalent among Blacks than whites. Vitamin D-binding protein (DBP) levels vary with race and may modulate "bioavailable" levels of 25(OH)D. OBJECTIVE: To determine the effect of DBP levels on the functional response to vitamin D. SETTING AND DESIGN: A randomized, placebo-controlled trial of vitamin D repletion for 2 mo, which took place at an outpatient research unit. Participants included 150 vitamin D-deficient (25(OH)D <20 ng/mL) adults. Participants were randomly assigned to receive either 50,000 IU of vitamin D3 or placebo weekly for 8 weeks. This is a post-hoc analysis using DBP, 25(OH)D, PTH, and calcium levels. RESULTS: Blacks had lower total 25(OH)D (12 vs 15 ng/mL, P < .001) and DBP levels (119 vs 234 µg/mL, P < .001) than non-Blacks. DBP levels were similar before and after vitamin D3 or placebo treatment (r = 0.98, P < .001). Baseline total 25(OH)D levels were a significant determinant of baseline PTH levels (P < .001). The change in total 25(OH)D was associated with the change in PTH (P < 0.001) and calcium levels (P < .05). In contrast, DBP levels were not a determinant of baseline PTH (P = .57) nor significantly related to changes in either PTH (P = .53) or calcium levels (P = .88). CONCLUSIONS: DBP levels are stable in Blacks and non-Blacks, and do not change with correction of vitamin D deficiency. Even for individuals with total 25(OH)D levels < 20 ng/mL, Blacks have significantly lower DBP levels than non-Blacks. However, within this range of total 25(OH)D, DBP levels do not influence the effect of vitamin D repletion on PTH or calcium levels.

A pilot clinical study to evaluate changes in urine osmolality and urine cAMP in response to acute and chronic water loading in autosomal dominant polycystic kidney disease.

BACKGROUND AND OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD) leads to kidney failure in half of those affected. Increased levels of adenosine 3':5'-cyclic monophosphate (cAMP) play a critical role in disease progression in animal models. Water loading, by suppressing arginine vasopressin (AVP)-stimulated cAMP production, is a proposed therapy for ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The effects of acute and sustained water loading on levels of urine osmolality (Uosm) and cAMP in 13 subjects with ADPKD and 10 healthy controls were studied. Uosm and cAMP concentrations were measured before and after water loading. RESULTS: Urine [cAMP] indexed to Uosm significantly decreased with acute water loading in both groups (58% in controls and 35% in ADPKD). Chronic water loading resulted in a nonsignificant 13% decrease in 24-hour urine cAMP excretion in ADPKD participants, despite an increase in 24-hour urine volume by 64% to 3.14 +/- 0.32 L and decrease in mean Uosm by 46%, to below that of plasma (270 +/- 21 mOsm/L). CONCLUSIONS: Increased water intake of 3 L per day decreased Uosm in most ADPKD subjects. While urine [cAMP] accurately reflects changes in Uosm during acute water loading in ADPKD subjects, chronic water loading did not lower 24-hour urine cAMP excretion, although subjects with higher baseline [cAMP] (>2 nmol/mg Cr) responded best. Decreases in urine [cAMP] and osmolality are consistent with decreased AVP activity. These results support the need for a larger study to evaluate the effect of chronic water loading on ADPKD progression.

Moderate kidney disease inhibits atherosclerosis regression.

UNLABELLED: Chronic kidney disease (CKD) accelerates cardiovascular disease. The mechanisms that explain this independent, excess risk associated with CKD have not been fully elucidated. OBJECTIVES: We propose that impaired regression of atherosclerosis in renal disease represents a novel risk factor for the heightened morbidity and mortality and resistance to treatment observed in patients with CKD. METHODS AND RESULTS: Using a transplant model to study atherosclerosis regression, we transplanted atheromatous aortic segments generated in Apolipoprotein E knock-out (ApoE(-/-)) mice, into either control or moderately uremic, normolipidemic, wild-type mice. In non-uremic mice, lesions regressed 55%, whereas lesions in uremic mice increased in size by 17% (p<0.01 for control vs. uremic). The lesions in uremic mice were also characterized by a greater presence of macrophages (36,300 microm(2) vs. 12,600 microm(2), p<0.01). This finding was despite upregulation of chemokine receptor 7 (CCR7), normally a migration factor, in uremic lesion macrophages. Gene expression analysis of lesion macrophages showed relative down-regulation of serum response factor (SRF) target genes in the uremic group, consistent with impaired CCR7 signaling. CONCLUSION: Moderate kidney disease inhibits regression of atherosclerosis in a mouse transplant model. This inhibition may be a result of impaired CCR7 signaling.

The Notch pathway in podocytes plays a role in the development of glomerular disease.

Albuminuria associated with sclerosis of the glomerulus leads to a progressive decline in renal function affecting millions of people. Here we report that activation of the Notch pathway, which is critical in glomerular patterning, contributes to the development of glomerular disease. Expression of the intracellular domain of Notch1 (ICN1) was increased in glomerular epithelial cells in diabetic nephropathy and in focal segmental glomerulosclerosis. Conditional re-expression of ICN1 in vivo exclusively in podocytes caused proteinuria and glomerulosclerosis. In vitro and in vivo studies showed that ICN1 induced apoptosis of podocytes through the activation of p53. Genetic deletion of a Notch transcriptional partner (Rbpj) specifically in podocytes or pharmacological inhibition of the Notch pathway (with a gamma-secretase inhibitor) protected rats with proteinuric kidney diseases. Collectively, our observations suggest that Notch activation in mature podocytes is a new mechanism in the pathogenesis of glomerular disease and thus could represent a new therapeutic target.