Effect of finerenone on nephrotic syndrome in patients with diabetic kidney disease.

Introduction: Diabetic kidney disease (DKD) is an important complication of diabetes as it results in end-stage renal disease; hence, several drugs have been developed for its treatment. However, even with treatment with renin-angiotensin system inhibitors and sodium-glucose cotransporter-2 inhibitors, the residual risk of DKD remains. While this risk is an issue, the renoprotective effects of finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, are becoming evident. High proteinuria increases the risk of cardiovascular death as well as renal failure. Hence, it is especially important to address cases of urine protein to nephrotic levels in DKD, however, no previous studies have assessed the safety and efficacy of finerenone in patients with DKD and nephrotic syndrome. Therefore, this study aimed to assess whether finerenone has a renoprotective effect in advanced DKD complicated by nephrotic syndrome. Methods: Nine patients with DKD and nephrotic syndrome who received 10-20 mg/day of finerenone were retrospectively analyzed. The average observation period was 9.7 ± 3.4 months. Patients with serum potassium levels greater than 5.0 mEq/L at the start of finelenone were excluded. Changes in urinary protein levels, estimated glomerular filtration rate (eGFR), and serum potassium levels were studied before and after finerenone administration. Results: The mean changes in the urinary protein creatinine ratio (UPCR) at baseline were 6.6 ± 2.0. After finerenone treatment, the mean UPCR decreased to -0.6 ± 3.9; however, this change was not statistically significant.The eGFR decline slope also tended to decrease with finerenone treatment (before vs. after: 3.1 ± 4.9 vs. -1.7 ± 3.2 mL/min/1.73 m2. Furthermore, finerenone did not increase serum potassium levels. Conclusions: Patients treated with finerenone showed decreased UPCR; hence, it is suggested that finerenone may be effective in treating nephrotic syndrome in patients with DKD. These findings may be applicable to real-world clinical settings. Nonetheless, it is important to note that this study was a retrospective analysis of a single-center cohort and had a limited sample size, highlighting the need for additional large-scale investigations.

Effect of finerenone on diabetic kidney disease outcomes with estimated glomerular filtration rate below 25 mL/min/1.73 m2.

Background: In the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease trial, finerenone reduced the risk of cardiovascular events in patients with chronic kidney disease (CKD) and type 2 diabetes, while in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial, it improved renal and cardiovascular outcomes in patients with advanced CKD. However, no previous studies have assessed patients with CKD and type 2 diabetes with an estimated glomerular filtration rate (eGFR) below 25 mL/min/1.73 m2. Methods: Nine patients with CKD and type 2 diabetes who received finerenone 10 mg/day were analyzed retrospectively. Changes in eGFR, urinary protein, and serum potassium levels were studied from 1 year before administration of finerenone until 6 months after administration. Results: The mean baseline eGFR slope was -7.63 ± 9.84 (mL/min/1.73 m2/year). After finerenone treatment, the mean eGFR slope significantly improved -1.44 ± 3.17 (mL/min/1.73 m2/6 months, P=0.038). However, finerenone treatment did not significantly reduce proteinuria. Furthermore, finerenone did not increase serum potassium levels. Conclusions: Patients treated with finerenone showed a significantly slower decline in eGFR. Furthermore, aside from the present study, no reports have indicated the effectiveness of finerenone in patients with advanced CKD with an eGFR below 25 mL/min/1.73 m2. As confirmed in our clinical trials, the finding that finerenone is effective in a wide range of renal functions can be generalized to clinical practice. However, sample size in this study was small. Thus, further large-scale investigations will be needed.

Current findings on the efficacy of incretin-based drugs for diabetic kidney disease: A narrative review.

Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease (CKD), leading end-stage renal disease. Thus, DKD is one of the most important diabetic complications. Incretin-based therapeutic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonizts and dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to elicit vasotropic actions, suggesting a potential for effecting reduction in DKD. Glucose-dependent insulinotropic polypeptide (GIP) is also classified as an incretin. However, the insulin action after GIP secretion is known to be drastically reduced in patients with type 2 diabetes. Therefore, GIP has been formally considered unsuitable as a treatment for type 2 diabetes in the past. This concept is changing as it has been reported that resistance to GIP can be reversed and its effect restored with improved glycemic control. The development of novel dual- or triple- receptor agonizts that can bind to the receptors, not only for GLP-1 but also to GIP and glucagon receptors, is intended to simultaneously address several metabolic pathways including protein, lipid, and carbohydrate metabolism. These led to the development of GIP receptor agonist-based drugs for type 2 diabetes. The possibility of combined GIP/GLP-1 receptor agonist was also explored. The novel dual GIP and GLP-1 receptor agonist tirzepatide has recently been launched (Mounjaro®, Lilly). We have revealed precise mechanisms of the renoprotective effect of GLP-1 receptor agonizts or DPP-4 inhibitors, while the long-term effect of tirzepatide will need to be determined and its potential effects on kidneys should be properly tested.

Predictive significance of glomerular insulin receptor substrate-1 in patients with diabetic kidney disease.

Background: In rodents, glomerular expression of insulin receptor substrate 1 (IRS1) is decreased in diabetic kidney disease (DKD) and reduced associated functioning is involved in the development and progression of DKD. This study aimed to evaluate the significance of glomerular IRS1 expression in DKD patients, and investigated whether glomerular IRS1 expression can reflect renal pathology and predict renal outcomes. Methods: This study included 10 patients who underwent renal biopsy and were diagnosed with DKD or minor glomerular abnormality (MGA). IRS1-positive cells were determined based on renal biopsy and immunostaining, and the associations of the number of these cells with baseline and prognostic parameters were analyzed. Results: IRS1-positive cells were significantly decreased in DKD than in MGA. IRS1 positivity tended to be negatively correlated with global glomerulosclerosis and tubulointerstitial fibrosis. The rate of change in estimated glomerular filtration rate before and 12 months after renal biopsy was positively correlated to the number of IRS1-positive cells. Furthermore, a tendency towards negative correlation was observed between the number of glomerular IRS1-positive cells and the proteinuria. Conclusions: This study shows the glomerular IRS1-positive cell count was significantly decreased in DKD, and that the degree IRS1 positivity was partially correlated with renal pathology and function.

Effects of incretin-based therapeutic agents including tirzepatide on renal outcomes in patients with type 2 diabetes: A systemic review and meta-analysis.

Background: This meta-analysis was conducted to investigate the effects of incretin-based therapeutic agents, including the latest agent tirzepatide, on renal outcomes in patients with type 2 diabetes. Methods: MEDLINE (via PubMed) and Cochrane databases were searched for studies involving incretin-based therapeutic agents up to July 2022. Randomized and controlled trials comparing incretin-based therapeutic agents with placebo or other antidiabetic agents, and reporting renal outcomes were selected. The inclusion criteria were items related to the effects on albuminuria and the kidney-specific composite outcomes. A network meta-analysis was conducted to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Twelve trials consisting of 75,346 participants were included in this meta-analysis. Glucagon-like peptide-1 (GLP-1) receptor agonists reduced the risk of the kidney-specific composite outcome by 21% (HR 0.79, 95% CI 0.75-0.85), and worsening albuminuria by 24% (HR 0.76, 95% CI 0.71-0.82). In particular, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide remarkably reduced the risk of the kidney-specific composite outcome by 45% (HR 0.55, 95% CI 0.40-0.77), and worsening albuminuria by 62% (HR 0.38, 95% CI 0.24-0.61). Conclusions: Among incretin-based therapeutic agents, tirzepatide was associated with a significantly reduced risk of diabetic kidney disease.

Multicentric IL-5-positive Castleman Disease With Nephrotic Syndrome Relapsed After Rituximab Treatment.

BACKGROUND/AIM: To date, no reports of interleukin (IL)-5-producing Castleman disease with nephrotic syndrome and moreover no reports of relapse after remission with rituximab treatment, have been published. CASE REPORT: A 67-year-old male presented to the Osaka Medical and Pharmaceutical University Hospital with a history of low-grade fever, papules, and nephrotic syndrome. Lymph nodes were palpated in the inguinal region. The patient showed anemia, eosinophilia, polyclonal hypergammaglobulinemia, and elevated interleukin (IL)-6 levels. Patient's serum IL-5 and IL-6 levels were measured using ELISA and immunohistochemical staining of lymph nodes was performed with antibodies specific to CD134. Histological examination confirmed diagnosis of a plasma cell variant of Castleman disease. After a total of four weekly doses of rituximab, urinary protein disappeared, and skin symptoms improved. However, one month after rituximab treatment, the skin rash worsened again, and eosinophils and IL-5 were elevated significantly. CONCLUSION: This is the first report of recurrent Castleman disease with direct evidence of increased serum IL-5. It may be reasonable to use rituximab, an anti-CD20 antibody for treating the disease, however, for IL-5-producing cases the effect of rituximab may be partial.

In vitro methods to ensure absence of residual undifferentiated human induced pluripotent stem cells intermingled in induced nephron progenitor cells.

Cell therapies using human induced pluripotent stem cell (hiPSC)-derived nephron progenitor cells (NPCs) are expected to ameliorate acute kidney injury (AKI). However, using hiPSC-derived NPCs clinically is a challenge because hiPSCs themselves are tumorigenic. LIN28A, ESRG, CNMD and SFRP2 transcripts have been used as a marker of residual hiPSCs for a variety of cell types undergoing clinical trials. In this study, by reanalyzing public databases, we found a baseline expression of LIN28A, ESRG, CNMD and SFRP2 in hiPSC-derived NPCs and several other cell types, suggesting LIN28A, ESRG, CNMD and SFRP2 are not always reliable markers for iPSC detection. As an alternative, we discovered a lncRNA marker gene, MIR302CHG, among many known and unknown iPSC markers, as highly differentially expressed between hiPSCs and NPCs, by RNA sequencing and quantitative RT-PCR (qRT-PCR) analyses. Using MIR302CHG as an hiPSC marker, we constructed two assay methods, a combination of magnetic bead-based enrichment and qRT-PCR and digital droplet PCR alone, to detect a small number of residual hiPSCs in NPC populations. The use of these in vitro assays could contribute to patient safety in treatments using hiPSC-derived cells.

Prediction of decreased estimated glomerular filtration rate using liver fibrosis markers: a renal biopsy-based study.

Non-alcoholic fatty liver disease is the most common chronic liver disease and is associated with chronic kidney disease. The fibrosis-4 index and non-alcoholic fatty liver disease score are widely used as non-invasive diagnostic methods for non-alcoholic fatty liver disease. However, the relationship between these markers and specific renal histopathologies in chronic kidney disease remain unclear. This study included 179 patients aged between 16 and 80 years who underwent renal biopsy. We examined the association between the fibrosis-4 index or non-alcoholic fatty liver disease score and change in estimated glomerular filtration rate 12 months after kidney biopsy for each renal histopathology. Renal histopathologies were determined by renal biopsy. Our results showed that there was a significant negative correlation between the fibrosis-4 index and estimated glomerular filtration rate. In nephrosclerosis, the non-alcoholic fatty liver disease score and estimated glomerular filtration rate tended to have a negative correlation, albeit without significance. In IgA nephropathy, both the fibrosis-4 index and non-alcoholic fatty liver disease score were significantly negatively correlated with estimated glomerular filtration rate. Furthermore, the fibrosis-4 index was not associated with urinary protein-to-creatinine ratio or renal function markers such as urinary b2 microglobulin and urinary N-acetyl-D-glucosamine. Our kidney biopsy-based study showed that the liver fibrosis markers fibrosis-4 index and non-alcoholic fatty liver disease score were negatively correlated with the estimated glomerular filtration rate in nephrosclerosis and IgA nephropathy.

Treatment of Renal Anemia in Patients With Hemodialysis Using Hypoxia-inducible Factor (HIF) Stabilizer, Roxadustat: A Short-term Clinical Study.

BACKGROUND/AIM: Renal anemia is a major complication in patients with chronic kidney disease (CKD) and hemodialysis, increasing morbidity and mortality. Roxadustat is a novel oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), which is administrated for renal anemia. Different from erythropoiesis-stimulating agents (ESAs), Roxadustat could increase erythropoietin physiologically, improving the therapeutic effects. It has not been so long since Roxadustat was approved by the European Commission (EC). Thus, only a few studies have reported on the treatment of renal anemia using Roxadustat. PATIENTS AND METHODS: In this study, we evaluated the efficacy of Roxadustat in patients undergoing hemodialysis (HD). Nine patients under HD (72±10 years old) were enrolled in this study. Patients received Roxadustat first time or changed from ESAs (5-10 mg, 3 times a week after HD). Observation period was 5.3±2.9 months. RESULTS: Roxadustat treatment effectively increased and maintained hemoglobin levels. Levels of ferritin and C-reactive protein tended to decrease, but the difference was not statistically significant. No significant adverse effects were observed in all patients during the study. CONCLUSION: Roxadustat is effective and relatively tolerant for treating renal anemia in patients subjected to hemodialysis.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney disease: Advantages and disadvantages.

Anemia is a common feature and complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and recombinant human erythropoietin have been used widely in renal anemia treatment. Recently, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) that may improve the treatment of renal anemia patients were launched. Previous studies indicated that HIF-PHIs may decrease hepcidin levels and modulate iron metabolism, thereby increasing total iron-binding capacity and reducing the need for iron supplementation. Furthermore, HIF-PHIs can reduce inflammation and oxidative stress in CKD. Recombinant erythropoietin has become a routine treatment for patients with CKD and end-stage renal disease with relatively few adverse effects. However, higher doses of recombinant erythropoietin have been demonstrated to be an independent predictor of mortality in patients under hemodialysis. Phase III clinical trials of HIF-PHIs in patients with anemia and dialysis-dependent CKD have shown their efficacy and safety in both non-dialysis and dialysis CKD patients. However, HIFα binds to specific hypoxia-response elements in the vascular endothelial growth factor or retinoic acid-related orphan receptor gamma t (RORγt) promoter, which may be involved in the progression of cancer, psoriasis, and rheumatoid arthritis. In this paper, we have summarized the mechanism, clinical application, and clinical trials of HIF-PHIs in the treatment of renal anemia and aimed to provide an overview of the new drugs in clinical practice, as well as reconsider the advantages and disadvantages of HIF-PHIs and ESAs. Presently, there are not enough clinical studies examining the effects of long-term administration of HIF-PHIs. Therefore, further studies will be needed.

Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes.

Diabetes-induced podocyte apoptosis is considered to play a critical role in the pathogenesis of diabetic kidney disease (DKD). We proposed that hyperglycaemia can induce podocyte apoptosis by inhibiting the action of podocyte survival factors, thus inactivating the cellular effects of insulin signalling. In this study, we aimed to determine the effects of linagliptin on high glucose-induced podocyte apoptosis. Linagliptin reduced the increase in DNA fragmentation as well as the increase in TUNEL-positive cells in podocytes induced by high-glucose condition. Furthermore, linagliptin improved insulin-induced phosphorylation of insulin receptor substrate 1 (IRS1) and Akt, which was inhibited in high-glucose conditions. Adenoviral vector-mediated IRS1 overexpression in podocytes partially normalised DNA fragmentation in high-glucose conditions, while downregulation of IRS1 expression using small interfering RNA increased DNA fragmentation even in low-glucose conditions. Because reactive oxygen species inhibit glomerular insulin signalling in diabetes and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important intrinsic antioxidative systems, we evaluated whether linagliptin increased Nrf2 in podocytes. High-glucose condition and linagliptin addition increased Nrf2 levels compared to low-glucose conditions. In summary, linagliptin offers protection against DKD by enhancing IRS1/Akt insulin signalling in podocytes and partially via the Keap1/Nrf2 pathway. Our findings suggest that linagliptin may induce protective effects in patients with DKD, and increasing IRS1 levels could be a potential therapeutic target in DKD.

Incidence of acute kidney disease after receiving hematopoietic stem cell transplantation: a single-center retrospective study.

BACKGROUND: Previous reports have shown that acute kidney injury (AKI) is common after hematopoietic stem cell transplantation (HSCT), which is a crucial treatment for patients with hematological disorders. AKI could increase mortality and induce adverse effects including the development of chronic kidney disease. The incidence of AKI in association with HSCT reportedly varies significantly because several definitions of AKI have been adopted. Acute kidney disease (AKD) is a new concept that can clinically define both AKI and persistent decreases in glomerular filtration rate (GFR) state. We conducted a retrospective cohort study to determine the incidence of AKD after HSCT. METHODS: This study included 108 patients aged between 16 and 70 years undergoing HSCT. In this study, AKD included clinical condition of AKI or subacute decreases in GFR. AKI was defined according to the Kidney Disease: Improving Global Outcomes guidelines based on serum creatinine. However, urine output data were not included to define AKI because the database lacked some of these data. Comparisons were made between groups using the Mann-Whitney U test. RESULTS: Acute kidney disease occurred in 17 patients (15.7%). There were significant differences between the AKD and non-AKD with respect to ABO-incompatible HSCT (p = 0.001) and incidence of acute graft versus host disease (GVHD) after HSCT (p < 0.001). The 100-day overall survival of patients with AKD and without AKD after HSCT was 70.6% and 79.8%, respectively (p = 0.409). DISCUSSION: ABO-incompatible HSCT and acute GVHD after HSCT were risk factors for the incidence of AKD. However, we could not find a significant association between AKD after HSCT and mortality.

Treatment of secondary hyperparathyroidism in patients on hemodialysis using a novel synthetic peptide calcimimetic, etelcalcetide: a short-term clinical study.

OBJECTIVE: Secondary hyperparathyroidism (SHPT) is a major complication in patients with chronic kidney disease (CKD). SHPT is related to chronic kidney disease-mineral bone disorder, leading to increased morbidity and mortality. Etelcalcetide is intravenously administered at the end of hemodialysis (HD). Etelcalcetide differs from the oral calcimimetic cinacalcet because it reduces gastrointestinal adverse events, thereby improving therapeutic effects. Etelcalcetide has only been approved by the U.S. Food and Drug Administration for several months. Therefore, there have only been a few reports regarding treatment of SHPT using etelcalcetide. This study aimed to evaluate the efficacy of etelcalcetide in patients on HD with SHPT. METHODS: Nine patients on HD (four men and five women, aged 58 ± 10 years) were enrolled in this study. All of the patients received etelcalcetide (5-10 mg, three times a week after HD). The observation period was 4.4 ± 1.0 months. RESULTS: All of the patients showed a significant reduction in serum parathyroid hormone levels during the observation period (-59% ± 20%). No significant adverse effects were observed. CONCLUSIONS: Although this study had an uncontrolled small group and a short observation period, our results suggest that etelcalcetide could be a promising agent for SHPT treatment.

Successful treatment of nephrotic syndrome induced by lambda light chain deposition disease using lenalidomide: A case report and review of the literature
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BACKGROUND: Light chain deposition disease (LCDD) is a monoclonal immunoglobulin deposition disease (MIDD) that is characterized by the deposition of monoclonal light chains in multiple organs, including the kidney. It is a rare disorder caused by an underlying monoclonal plasma cell dyscrasia. LCDD with renal involvement causes proteinuria, which sometimes can lead to nephrotic syndrome. The monoclonal light chains are mostly in the κ form. Treatment of LCDD is the same as that for multiple myeloma (MM); however, some conventional anticancer drugs show substantial toxicity and therefore cannot be administered to older patients or those with renal impairment. CASE PRESENTATION: An 80-year-old woman was referred to our department with severe nephrotic syndrome (13.6 g/gCr) and anemia. A renal biopsy showed mesangial proliferation and mesangial matrix expansion, and immunohistochemistry showed positive staining for λ chains along the glomerular basement membrane, but was negative for κ chains or amyloid deposition. A bone marrow biopsy revealed 64% plasma cells. Immunoglobulin G (IgG)-λ type M protein was detected, and the levels of free λ chain was significantly increased. We concluded that her nephrotic syndrome was caused by LCDD, which resulted from IgG-λ MM. The induction of a BCD (bortezomib, cyclophosphamide, and dexamethasone) treatment regimen did not lead to a hematological response or decrease in proteinuria. The administration of combination therapy of lenalidomide and prednisolone led to the successful reduction of proteinuria and hematuria. CONCLUSIONS: We presented a very rare case report describing the successful treatment of LCDD (λ chain)-induced nephrotic syndrome with lenalidomide.
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Methotrexate induced pneumatosis intestinalis under hemodialysis patient.

Pneumatosis intestinalis (PI) is a rare disorder characterized by the gas within the intestinal mucosa. This is the first report methotrexate (MTX) induced PI under hemodialysis (HD) patient. A 46-year-old man suffered rheumatoid arthritis and underwent HD at local HD center. After the initial induction of MTX, the patient showed epigastralgia and diarrhea. He was referred to our hospital and abdominal computed tomography showed significant large intestinal edema and free intraperitoneal air consistent with PI. Physicians should aware that MTX is contraindication drug for chronic kidney disease and high-flux HD may decrease MTX toxicity and oxidative stress, improving PI.

Conditional Deletion of Smad1 Ameliorates Glomerular Injury in Progressive Glomerulonephritis.

Matrix expansion and cell proliferation are concomitantly observed in various glomerular injuries. However, the molecular mechanisms responsible for these changes have not been fully elucidated. We have reported that Smad1 is a key signalling molecule that regulates the transcription of type IV collagen (Col4) in mesangial matrix expansion and is thereby involved in glomerular injury in an acute model of glomerulonephritis. In this study, we addressed the role of Smad1 signalling in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis, using conditional deletion of Smad1 in Rosa26CreERT2 mice (Smad1-CKO). Mesangial matrix expansion in the Smad1-CKO mice with NTN was significantly inhibited compared with that in wild type mice with NTN, which was consistent with the decrease in Col4 expression level. On the other hand, STAT3 activation and cell proliferation were not influenced by Smad1 deletion in the NTN model. Therefore, we investigated another factor that activates cell proliferation in the absence of Smad1. Id2 induced VEGF secretion and subsequent STAT3 activation, independently of Smad1 expression in mouse mesangial cells. Here we show that Smad1 plays an important role in the development of glomerular injury without affecting cell proliferation, in progressive glomerulonephritis.

Overexpressing IRS1 in Endothelial Cells Enhances Angioblast Differentiation and Wound Healing in Diabetes and Insulin Resistance.

The effect of enhancing insulin's actions in endothelial cells (ECs) to improve angiogenesis and wound healing was studied in obesity and diabetes. Insulin receptor substrate 1 (IRS1) was overexpressed in ECs using the VE-cadherin promoter to create ECIRS1 TG mice, which elevated pAkt activation and expressions of vascular endothelial growth factor (VEGF), Flk1, and VE-cadherin in ECs and granulation tissues (GTs) of full-thickness wounds. Open wound and epithelialization rates and angiogenesis significantly improved in normal mice and high fat (HF) diet-induced diabetic mice with hyperinsulinemia in ECIRS1 TG versus wild type (WT), but not in insulin-deficient diabetic mice. Increased angioblasts and EC numbers in GT of ECIRS1 mice were due to proliferation in situ rather than uptake. GT in HF-fed diabetic mice exhibited parallel decreases in insulin and VEGF-induced pAkt and EC numbers by >50% without changes in angioblasts versus WT mice, which were improved in ECIRS1 TG mice on normal chow or HF diet. Thus, HF-induced diabetes impaired angiogenesis by inhibiting insulin signaling in GT to decrease the differentiation of angioblasts to EC, which was normalized by enhancing insulin's action targeted to EC, a potential target to improve wound healing in diabetes and obesity.

Dual involvement of growth arrest-specific gene 6 in the early phase of human IgA nephropathy.

BACKGROUND: Gas6 is a growth factor that causes proliferation of mesangial cells in the development of glomerulonephritis. Gas6 can bind to three kinds of receptors; Axl, Dtk, and Mer. However, their expression and functions are not entirely clear in the different glomerular cell types. Meanwhile, representative cell cycle regulatory protein p27 has been reported to be expressed in podocytes in normal glomeruli with decreased expression in proliferating glomeruli, which inversely correlated with mesangial proliferation in human IgA nephropathy (IgAN). METHODS: The aim of this study is to clarify Gas6 involvement in the progression of IgAN. Expression of Gas6/Axl/Dtk was examined in 31 biopsy proven IgAN cases. We compared the expression levels with histological severity or clinical data. Moreover, we investigated the expression of Gas6 and its receptors in cultured podocytes. RESULTS: In 28 of 31 cases, Gas6 was upregulated mainly in podocytes. In the other 3 cases, Gas6 expression was induced in endothelial and mesangial cells, which was similar to animal nephritis models. Among 28 podocyte type cases, the expression level of Gas6 correlated with the mesangial hypercellularity score of IgAN Oxford classification and urine protein excretion. It also inversely correlated with p27 expression in glomeruli. As for the receptors, Axl was mainly expressed in endothelial and mesangial cells, while Dtk was expressed in podocytes. In vitro, Dtk was expressed in cultured murine podocytes, and the expression of p27 was decreased by Gas6 stimulation. CONCLUSIONS: Gas6 was uniquely upregulated in either endothelial/mesangial cells or podocytes in IgAN. The expression pattern can be used as a marker to classify IgAN. Gas6 has a possibility to be involved in not only mesangial proliferation via Axl, but also podocyte injury via Dtk in IgAN.

Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-ß isoform in the endothelium.

RATIONALE: Loss of insulin action in the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes mellitus can activate protein kinase C-ß isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase/Akt pathway to inhibit the activation of endothelial nitric oxide synthase and metabolic actions. OBJECTIVE: To demonstrate that overexpressing protein kinase C-ß2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta. METHODS AND RESULTS: Protein kinase C-ß2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell cadherin. These mice were cross-bred with apoE-/- mice [Tg (Prkcb)apoE-/-]. On a Western diet, Tg(Prkcb)apoE-/- and apoE-/- mice did not differ in systemic insulin sensitivity, glucose tolerance, plasma lipid, or blood pressure. Insulin action in endothelial cells and femoral artery from Tg(Prkcb)apoE-/- mice was impaired by ≈40% with respect to Akt/endothelial nitric oxide synthase activation, and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)apoE-/- mice compared with that from apoE-/- mice. Basal and angiotensin-stimulated big endothelin-1 levels were elevated in Tg(Prkcb)apoE-/- mice compared with apoE-/- mice. The severity of atherosclerosis in the aorta from Tg(Prkcb)apoE-/- mice increased by ≈70% as measured by en face fat staining and plaque content of the number of smooth muscle cells, macrophages, and extracellular matrix. CONCLUSIONS: Specific protein kinase C-ß2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis because of loss of insulin-stimulated Akt/endothelial nitric oxide synthase activation and angiotensin-induced increases in endothelin-1 expression.

Diabetic nephropathy: protective factors and a new therapeutic paradigm.

Diabetic nephropathy (DN) is the most common cause of chronic kidney disease (CKD) and its number has been increasing. CKD is a worldwide threat to health but the precise mechanism of this problem is not fully appreciated. It is believed that hyperglycemia is one of the most important metabolic factors in the development of DN. Multiple molecular mechanisms have been proposed to mediate hyperglycemia's adverse effects on kidney. To identify targets for therapeutic intervention, most studies have focused on understanding how abnormal levels of such metabolities cause DN. However, there have been few reports regarding endogenous renal protective factors. Thus, recognition of the importance of this could be providing a new perspective for understanding the development of DN and a new therapeutic paradigm to combat DN.