Chronic Glomerular Disease Research Articles

Relationship Between Type of Hypertension and Renal Arteriolosclerosis in Chronic Glomerular Disease

Background/Aims: Hypertension (HT) is a common complication in patients with chronic kidney disease (CKD). However, the relationship between circadian rhythm disorder of blood pressure (BP) and intra-renal damage remains unclear. Methods: Ninety patients with chronic glomerular disease (CGD) were included in the present study. On the basis of the clinic BP (CBP) and 24 h-ambulatory BP (ABP) measurements, the patients were divided into the following groups; normotension (NT), white coat HT (WHT), masked HT (MHT), and sustained HT (SHT). For renal histopathological assessment, we evaluated each biopsy specimen for sclerotic glomeruli (SG), interstitial fibrosis (IF), intimal thickening of intra-lobular arteries (ILA), and arteriolar hyalinosis (AH). Results: The prevalence of NT, WHT, MHT and SHT was 60.0%, 3.3%, 23.3%, and 13.4%, respectively. Compared with circadian BP pattern, all-day HT was most prevalent in the SHT group, whereas nighttime HT was most prevalent in the MHT group. The results of histological analysis showed that the SHT group had more severe SG and IF and the MHT group had more severe IF compared to the NT group. As for renal arteriolosclerosis, the MHT and SHT groups had more severe AH compared with the NT group, whereas ILA was comparable among all four groups. Furthermore, multivariate analysis revealed that ILA was significantly correlated only with age, whereas AH was significantly correlated with age and HT based on ABP, but not HT based on CBP. Conclusions: Our findings suggest that renal AH was severe not only in the SHT group, but also in the MHT group. Careful ABP monitoring should be recommended in patients with CGD.

Oral conditions, periodontal status and periodontal treatment need of chronic kidney disease patients

Objective: To evaluate the periodontal status and periodontal treatment need (TN) of patients with chronic kidney disease (CKD). Methodology: All the patients with CKD who presented at the renal out-patient clinic of the University of Lagos University Teaching Hospital were recruited into the study. Data were collected using self-administered questionnaire with open and closed questions comprising demographic details such as age and gender, year of diagnosis, and stage of kidney disease and dialysis. Simplified oral hygiene index (OHI-S) of Green and Vermilion and Community Periodontal Index of TN were used to assess the patients' periodontal status. Results: Participants' age ranged between 21 years and 73 years with a mean age of 45.14 ΁ 14.14. Of the 65 participants, males were 64.6% and females were 35.5%. More than half of the participants were diagnosed within the last 5 years (54.6%). The cause of renal disease in 41 of them (63.1%) was hypertension. Other causes such as chronic glomerular nephritis (4.6%), diabetes mellitus (4.6%), and hypertensive heart disease (3.1%) were also mentioned. Nearly, 6.2% had no known cause. About a fifth of the participants (16.9%) had other systemic conditions such as diabetes. Their mean OHI-S was 1.96 ΁ 0.90. About two-thirds of the participants had CPI score of 2, and the major treatment needed was code 2 consisting of scaling, polishing, and root planing. Conclusion: Majority of the CKD patients reviewed had poor periodontal status with code 2 TN. We, therefore, recommend nonsurgical periodontal treatment for all CKD patients to improve their oral health and forestall the systemic effects of periodontal pathology.

Patterns of glomerular disease based on 4-year kidney biopsy material analyzed by light microscopy and immunofluorescence: a retrospective single-center analysis in Poland.

The aim of this study was to assess the epidemiology of different patterns of chronic glomerular diseases based on clinical, histopathological and immunofluorescent findings of glomerulonephritis patients hospitalized in the Department of Nephrology, Transplantology and Internal Diseases in Poznan between January 2009 and December 2012. We retrospectively studied 418 patients who had been subjected to renal biopsies. Data on serum creatinine concentration, 24 h proteinuria, arterial hypertension, diabetes mellitus, and histological and immunofluorescent findings were collected. The patients' mean age was 42 ±15. The male sex prevailed (53.1%). Immunoglobulin A nephropathy was the most common finding (18.9%), followed by focal segmental glomerulosclerosis (16.3%), membranous glomerulonephritis (10.1%), lupus nephritis (8.4%), extracapillary glomerulonephritis (3.3%) and membranoproliferative glomerulonephritis (2.6%). In 69 (16.5%) patients the biopsy was non-informative or non-diagnostic. Patients with membranous nephropathy presented the highest frequency of nephrotic syndrome (71.4%), followed by membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis. Combined analysis of the clinical, histopathological and immunofluorescent findings in glomerulonephritis patients based on a single center's data can provide important epidemiological findings.

Replenishment of the podocyte compartment by parietal epithelial cells

While progressive podocytopenia is a characteristic feature of chronic glomerular disease, the visceral epithelial niche can be replenished from the parietal epithelium. Two new reports demonstrate this process in genetically engineered mice, using fate mapping, and in human renal biopsies manifesting segmental glomerulosclerosis in diverse settings, using cellular and extracellular matrix markers.

65-Year-Old Woman With Intermittent Fevers, Lower Extremity Paresthesia, Weight Loss, and Malaise

65-Year-Old Woman With Intermittent Fevers, Lower Extremity Paresthesia, Weight Loss, and Malaise

The inhibitory effect of angiotensin II on BKCa channels in podocytes via oxidative stress.

Angiotensin II (Ang II) is an important active substance of the renin-angiotensin system (RAS). The present study has confirmed that abnormalities of Ang II may be related with cerebrovascular diseases, endocrine diseases, cardiovascular diseases, liver diseases, such as: cerebral hypoxia, diabetes, obesity, atrial fibrillation, and liver cirrhosis. However, understanding effects of Ang II on podocytes is not enough. This study was to investigate the effects of oxidative stress on the large conductance, Ca(2+)-activated K(+) channels (BKCa). Results from the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay showed that Ang II induced podocyte death in a concentration-dependent manner. The measurement of superoxide dismutase (SOD) generation demonstrated that Ang II decreased the total SOD of cellular levels. Meaningfully, pretreatment of a type of ROS scavenger formulations named N-(mercaptopropionyl)-glycine (N-MPG) could inhibit podocyte apoptosis induced by Ang II. Meanwhile, patch-clamp technique was used in this study to detect the effects of Ang II on currents of BKCa channel in podocytes. The results indicated that Ang II inhibited the current amplitude of BKCa channel and decreased the slope of I-V curve. Ang II also made the activation curves of BKCa channel shift to the left. These results may provide a theoretical basis for potential treatment of chronic glomerular disease in the future.

Comparison of Azathioprine vs Mycophenalate Based Induction Free Protocol and One Year Renal Allograft Survival: Retrospective Single Center Study.

Aim: To retrospectively evaluate the one year graft survival in our renal transplant recipients on induction free immunosuppression protocol, between Azathioprine vs Mycophenalate Mofetil based regimen. Materials and Methods: Renal transplant patients from April 2000 to November 2012 were retrospectively evaluated. The demographic characteristics, the nature of transplant, donor relationship, degree of matching, immunosuppression protocol, were analyzed. All patients received induction free immunosuppression with Cyclosporine and Prednisolone with either Azathioprine (protocol I) or Mycophenolate Mofetil (protocol II). Patients who did not complete one year followup and those who received induction were excluded. Data was analyzed using SPSS 17. Results: 213 (174 males, 39 females) were included in the study. The mean age at transplant was 37.5 ± 11 years.The common reasons for chronic kidney diseases was 30 (14%) diabetes, 32 (15%) hypertension,89 (41.7%) chronic glomerular disease and 39 (18.3%) chronic interstitial nephritis. 201 (94.3%) were live related, and 12 (5.6%) were cadaver donors. Mother 44 (21.8%), sister 45 (22.3%), wife 37 (18.4%) and brother 17 (8.4%) were the common donors. Donor HLA Class I matching profiles showed 14 (9.7%) four antigen match, 7 (4.8%) triple antigen match, 97 (67.8%) haplomatch, 25 (17.4%) single antigen and 70 (48.9%) mismatches. 201 (94.3 %) patients graft survived at the end of one year. Protocol I was followed in 138 (64.7%) and protocol II in 75 (35.2%) recipients. Multivariate analysis of the data showed no significant difference in age, matching profile, basic disease among the two protocols. The protocol I had 133 (96.3%) functioning graft and 5 (3.6%) graft losses at the year end. Protocol II showed functioning graft in 68 (90.6%) and graft loss in 7 (9.4%) patients. There was no statistically significant difference in one year graft survival among two protocols (p= 0.804,NS). Conclusions: Our experience in Induction Free Immunosuppression regimen had shown good one year graft survival (94.3%), compared to any induction based protocols. We did not find any statistical difference among Azathioprine vs Mycophenolate Mofetil based protocols. This is very useful as Azathioprine based protocols are cost effective with comparable graft outcomes in Indian scenario, where majority of the patients pay for their treatment.

Significance of CD56+ Cell Aggregation in the Graft Following Kidney Transplantation.

Objective In the context of kidney transplantation, little is known about the involvement of natural killer (NK) cells in the immune reaction leading to either rejection or graft failure. We investigated the significance of CD56+ cell aggregation in human kidney transplant biopsies in regard of graft function and survival. Methods One hundred seventy-four clinically indicated transplant biopsies were included in this analysis. Immunohistochemical stainings for C4d and CD56 were performed and clinical correlation was assessed by serum creatinine and graft status. ResultsTen or more CD56+ cells/high power field (HPF) were associated with acute cellular rejection (P=0.001), chronic active antibody-mediated rejection (P<0.001), glomerular disease (P=0.022), and interstitial fibrosis and tubular atrophy (P=0.002). There was a significant positive correlation between the degree of C4d deposits and the number CD56+ cells (r=0.23, P=0.002). Compared with patients with 0 to 9 cells/HPF, those with 10 to 29 cells/HPF and those with greater than 30 cells/HPF had worse death-censored graft survival 1 year postbiopsy with a hazard ratio of 8.2 (95% CI 1.05-64.39, P=0.045) and 13.3 (95% CI 1.65-106.55, P=0.015), respectively in multivariate Cox regression. In addition, the postbiopsy mean levels of serum creatinine in patients with 10 or more cells/HPF were significantly higher than in those with 0 to 9 cells/HPF during the 1 year follow-up period which was confirmed by a linear mixed effect model (P<0.001). Conclusions CD56+ cell aggregation in human kidney transplant biopsies can be a predictive marker for graft function and survival.

Univariate and multiple linear regression analyses for 23 single nucleotide polymorphisms in 14 genes predisposing to chronic glomerular diseases and IgA nephropathy in Han Chinese.

Immunoglobulin A nephropathy (IgAN) is a complex trait regulated by the interaction among multiple physiologic regulatory systems and probably involving numerous genes, which leads to inconsistent findings in genetic studies. One possibility of failure to replicate some single-locus results is that the underlying genetics of IgAN nephropathy is based on multiple genes with minor effects. To learn the association between 23 single nucleotide polymorphisms (SNPs) in 14 genes predisposing to chronic glomerular diseases and IgAN in Han males, the 23 SNPs genotypes of 21 Han males were detected and analyzed with a BaiO gene chip, and their associations were analyzed with univariate analysis and multiple linear regression analysis. Analysis showed that CTLA4 rs231726 and CR2 rs1048971 revealed a significant association with IgAN. These findings support the multi-gene nature of the etiology of IgAN and propose a potential gene-gene interactive model for future studies.

Effect of spironolactone combined with angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers on chronic glomerular disease

The aim of the present study was to observe the effects of spironolactone on urine protein level and kidney function in patients with chronic glomerular disease receiving angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs). A total of 221 patients with chronic glomerular disease were divided into spironolactone and control groups. The spironolactone group was treated with spironolactone at a dose of 20 mg/day, in addition to the original treatment regime and doses of ACEIs and/or ARBs. The control group continuously received the original doses of ACEIs and/or ARBs alone. Twenty-four-hour urine protein levels, serum creatinine and potassium, plasma aldosterone (ALD) and blood pressure were monitored at 0, 4, 8, 12 and 16 weeks. The estimated glomerular filtration rates (eGFRs) were calculated based on the obtained serum creatinine results. Following treatment, the urine protein level in the spironolactone group was notably decreased compared with that prior to the treatment, whereas the urine protein level in the control group did not show a significant difference. No significant differences were observed with regard to the renal function, eGFR, serum potassium, plasma ALD and blood pressure in either group prior to and following treatment. In conclusion, spironolactone administration, when co-administered with ACEIs and/or ARBs, markedly decreases the urine protein levels in patients with chronic glomerular disease. The protective effect of spironolactone on renal function remains to be demonstrated.

A zebrafish model of conditional targeted podocyte ablation and regeneration

Podocytes are specialized cells that contribute critically to the normal structure and function of the glomerular filtration barrier. Their depletion plays an important role in the pathogenesis of glomerulosclerosis. Here, we report generation of a genetic model of conditional podocyte ablation and regeneration in zebrafish using a bacterial nitroreductase strategy to convert a prodrug, Metronidazole, into a cytotoxic metabolite. A transgenic zebrafish line was generated that expresses a green fluorescence protein (GFP) and the nitroreductase fusion protein under the control of the podocin promoter Tg(podocin:nitroreductase-GFP). Treatment of these transgenic zebrafish with Metronidazole results in podocyte apoptosis, a loss of nephrin and podocin expression, foot process effacement, and a leaky glomerular filtration barrier. Following Metronidazole washout, proliferating cells were detected in the glomeruli of recovering transgenic fish with a restoration of nitroreductase-GFP fluorescence, nephrin and podocin expression, a reestablishment of normal foot process architecture and glomerular barrier function. Thus, our studies show that zebrafish podocytes are capable of regenerating following depletion and establish the Tg(podocin:NTR-GFP) fish as a new model to study podocyte injury and repair.

Paracrine role for TGF-β-induced CTGF and VEGF in mesangial matrix expansion in progressive glomerular disease.

Transforming growth factor-β (TGF-β) is a key regulator of extracellular matrix (ECM), and may mediate the development of glomerulosclerosis with accumulation of mesangial matrix. Mesangial cells secrete TGF-β in response to common in vitro fibrogenic stimuli. Yet mesangial immunostaining for active TGF-β1 is frequently negative in chronic glomerular disease. TGF-β is rather expressed and/or activated by podocytes in both mesangial and podocyte diseases. Activated TGF-β/Smad signaling by podocytes may induce connective tissue growth factor (CTGF or CCN2) and vascular endothelial growth factor (VEGF) expression. Podocyte CTGF seems to have paracrine effects on mesangial cells to stimulate CTGF expression. CTGF appears to stimulate the fibronectin-matrix assembly via enhanced cell-surface expression of α5β1 integrin in the mesangium of diseased glomeruli. Podocyte VEGF-A overexpression also seems to play a paracrine role on mesangial cells to upregulate VEGF/VEGF receptor systems and to overproduce matrix proteins. Thus, paracrine CTGF and VEGF may contribute to mesangial matrix accumulation in chronic glomerular disease, culminating in the development of glomerulosclerosis. Together, these data bring new mechanistic insights into our understanding of the pathogenic role of TGF-β-induced CTGF and VEGF in mesangial matrix expansion in chronic progressive glomerular disease.

Hemodialysis in diabetics end-stage renal disease

Abstract Diabetes is the most common cause of new patients requiring renal replacement therapy (RRT), accounting for approximately 45% of cases in the US. Recent population-based study from North India, showed that the most common cause of chronic kidney disease (CKD) was diabetic nephropathy (DN) responsible for 41% of the cases. Many, but not all, nephrologists are of the opinion that RRT should be started earlier in diabetic than in non-diabetic patients, i.e. at an estimated glomerular filtration rate (eGFR) of approximately 15 mL/min. Hemodialysis (HD) is still the most common RRT modality in patients with diabetes. Failure of vascular access, intradialytic hypotension, high-risk of cardiovascular disease, retinopathy, amputation, and malnutrition are some common problems occurring among diabetic end-stage renal disease (ESRD) patients. Patient survival in diabetics on maintenance dialysis is lower than that seen in non-diabetics with end-stage renal failure due to chronic glomerular disease or hypertension cardiovascular disease is the most common cause of death, accounting for more than one-half of cases.

Urinary proteins as novel early diagnostic tools in preeclampsia?

Urinary proteins as novel early diagnostic tools in preeclampsia?

Correlation between glomerular filtration rate and urinary N acetyl-beta-D glucosaminidase in children with persistent proteinuria in chronic glomerular disease

PurposeUrinary excretion of N acetyl-beta-D glucosaminidase (NAG) and β2-microglobulin (β2-M) was increased in the presence of proximal tubular damage. Based on these urinary materials, we investigated the ability of expecting renal function in chronic glomerular diseases. In this study, we evaluated the relationship between glomerular filtration rate (GFR) urinary NAG, and urinary β2-M.MethodsWe evaluated 52 children with chronic kidney disease at the Chung-Ang University Hospital between January 2003 and August 2009. We investigated the 24-hour urinalysis and hematologic values in all 52 patients. Serum creatinine, creatinine clearance (Ccr), serum cystatin C, urinary β2-M and urinary NAG were measured.ResultsOut of 52 patients, there were 13 children with minimal change in disease, 3 children with focal segmental glomerulosclerosis, 17 children with immunoglobulin A nephropathy, 15 children with Henoch-Schönlein purpua nephritis, 3 children with poststreptococcal glomerulonephritis, and 1 child with thin glomerular basement membrane disease. In these patients, there were significant correlation between the Ccr and urinary NAG (r=-0.817; P<0.01), and between the GFR (as determined by Schwartz method) and urinary NAG (r=-0.821; P<0.01). In addition, there was a significant correlation between the GFR (as determined by Bokencamp method) and urinary NAG (r=-0.858; P<0.01).ConclusionIn our study, there was a significant correlation between the GFR and urinary NAG, but there was no correlation between the GFR and urinary β2-M, suggesting that the GFR can be predicted by urinary NAG in patients with chronic glomerular disease.

Proteinuria: From Molecular to Clinical Applications in Glomerulonephritis

Glomerular diseases including diabetic nephropathy are the leading cause of ESRD worldwide. Proteinuria, the hallmark of renal damage in glomerular diseases, is dependent on two main factors: the alteration of the glomerular filtration barrier and its three layers (glomerular endothelial cells, basement membrane, and visceral epithelial cells (podocytes)), and the impairment of proteins reabsorption by proximal tubular epithelial cells. In recent years there has been a great increase of knowledge of the molecular structure of glomerular filtration barrier and of the molecular mechanisms involved in tubular reabsorption of proteins. In this special issue the structure of the glomerular filter and the importance of glomerular talk in maintaining the integrity of the glomerular filtration barrier are reviewed by M. Menon et al. A. Tojo and S. Kinugasa reviewed the albumin glomerular permeability in normal and disease status and present their views of a possible mechanism of selective proteinuria in nephrotic syndrome of minimal change disease. A. Zhang and S. Huang summarized several molecular defects responsible for dysfunction of the glomerular filtration barrier. J. E. Toblli et al. overviewed the alterations of glomerular endothelial cells, basement membrane and podocytes, the possible relationship between glomerular proteinuria and tubulointerstitial damage, and described less and more recent approaches to reduce proteinuria. The review of J. R. Machado et al. summarizes the most important molecules involved in the pathogenesis of nephrotic syndrome. Galactose-deficient IgA1 is the hallmark of IgA nephropathy; in a cohort of 40 pediatric patients with biopsy-proven IgAN, a research group from the Le Bonheur Children's Hospital found no association between albuminuria and the galactose-deficiency, a finding that may question the pathologic role of galactose-deficiency in IgAN. The possible therapeutic efficacy of inhibition of mammalian target of rapamycin (mTOR) in primary mesangioproliferative glomerulonephritis was discussed by H. Trimarchi et al. who suggested prospective clinical trials. B. Zhang and W. Shi reviewed the therapeutic effects of cyclosporine A (CsA) in glomerulonephritis and evaluated the data in support of a nonimmunologic antiproteinuric effect of CsA dependent on a direct stabilization of podocyte cytoskeleton. The review by A. Cohen-Bucay and G. Viswanathan discusses nine additional urine biomarkers that may offer better prediction for the course of diabetic kidney disease progression than urinary albumin. The authors call for further longitudinal studies to validate the clinical value of these biomarkers to overcome the limitations of albuminuria. The great increase in knowledge of molecular biology of glomerular filtration barrier and tubular reabsorption of proteins has not been matched as yet by outcome prediction improvement and therapeutic advances. There is a need for further studies for better understanding the pathogenesis of proteinuria and the clinical value of the different urine biomarkers in diagnosis and management of patients with chronic glomerular diseases. Finally special thanks to the authors and the reviewers for their efforts to provide to the nephrology community a concise up-to-date knowledge on the pathogenesis and management of proteinuric kidney disease. Claudio Bazzi Omran Bakoush Loreto Gesualdo

Estrogen Receptor Alpha Expression in Podocytes Mediates Protection against Apoptosis In-Vitro and In-Vivo

Context/ObjectiveEpidemiological studies have demonstrated that women have a significantly better prognosis in chronic renal diseases compared to men. This suggests critical influences of gender hormones on glomerular structure and function. We examined potential direct protective effects of estradiol on podocytes.MethodsExpression of estrogen receptor alpha (ERα) was examined in podocytes in vitro and in vivo. Receptor localization was shown using Western blot of separated nuclear and cytoplasmatic protein fractions. Podocytes were treated with Puromycin aminonucleoside (PAN, apoptosis induction), estradiol, or both in combination. Apoptotic cells were detected with Hoechst nuclear staining and Annexin-FITC flow cytometry. To visualize mitochondrial membrane potential depolarization as an indicator for apoptosis, cells were stained with tetramethyl rhodamine methylester (TMRM). Estradiol-induced phosphorylation of ERK1/2 and p38 MAPK was examined by Western blot. Glomeruli of ERα knock-out mice and wild-type controls were analysed by histomorphometry and immunohistochemistry.ResultsERα was consistently expressed in human and murine podocytes. Estradiol stimulated ERα protein expression, reduced PAN-induced apoptosis in vitro by 26.5±24.6% or 56.6±5.9% (flow cytometry or Hoechst-staining, respectively; both p<0.05), and restored PAN-induced mitochondrial membrane potential depolarization. Estradiol enhanced ERK1/2 phosphorylation. In ERα knockout mice, podocyte number was reduced compared to controls (female/male: 80/86 vs. 132/135 podocytes per glomerulus, p<0.05). Podocyte volume was enhanced in ERα knockout mice (female/male: 429/371 µm3 vs. 264/223 µm3 in controls, p<0.05). Tgfβ1 and collagen type IV expression were increased in knockout mice, indicating glomerular damage.ConclusionsPodocytes express ERα, whose activation leads to a significant protection against experimentally induced apoptosis. Possible underlying mechanisms include stabilization of mitochondrial membrane potential and activation of MAPK signalling. Characteristic morphological changes indicating glomerulopathy in ERα knock-out mice support the in vivo relevance of the ERα for podocyte viability and function. Thus, our findings provide a novel model for the protective influence of female gender on chronic glomerular diseases.

Urinary excretion of liver-type fatty acid-binding protein as a marker of progressive kidney function deterioration in patients with chronic glomerulonephritis

BackgroundTo evaluate the value of basal urinary L-FABP (uL-FABP) excretion as a prognostic indicator of the progression of kidney function impairment in patients with chronic glomerulonephritis (CGN). MethodsOne hundred twenty-three patients with newly diagnosed, biopsy-proven primary CGN were included. In all patients, and in 28 healthy subjects, uL-FABP was measured using an ELISA. Risk factors of the progression of kidney function were evaluated. The patients were in follow-up for at least 5years. ResultsuL-FABP in the patients with CGN (76.58±17.3μg/g.cr) was greater than in the healthy subjects. A significant positive correlation between uL-FABP and proteinuria (R=0.501, P<0.01), serum creatinine (R=0.601, P<0.01) were found. Kaplan–Meier analysis revealed that uL-FABP >76.58μg/g.cr predicts progression of renal function. The cut off values for L-FABP at 119.8μg/g.cr was found to be more sensitive, area under the curve (AUC) was 0.95. ConclusionUrinary L-FABP may be a useful clinical biomarker for monitoring chronic glomerular disease. Urinary L-FABP can help predict the progression of chronic glomerular disease.

Role of mTOR in podocyte function and diabetic nephropathy in humans and mice.

Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy.

Angiotensinogen Expression Is Enhanced in the Progression of Glomerular Disease

Intrarenal renin-angiotensin system (RAS) activation plays a critical role in the development and progression of renal injury. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by multiple independent mechanisms. Angiotensinogen (AGT) is the only known substrate for renin that is a rate-limiting enzyme of the RAS. Recently, enhanced intrarenal AGT levels have been shown to reflect the intrarenal RAS status in hypertension, chronic glomerular disease and diabetic nephropathy. In this review, we focus on AGT expression of the diseased glomeruli in the progression of glomerular disease. An anti-glomerular basement membrane nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of AGT and Ang II. The addition of Ang II type 1 receptor blocker to CC-chemokine recaptor 2 antagonist markedly attenuated the induction of macrophage infiltration, AGT and Ang II, and reduced glomerular crescent formation. Next, the levels of glomerular AGT expression and marker of reactive oxygen species in Zucker diabetic fatty (ZDF) obese rats were higher than those in ZDF lean rats. Hydrogen peroxide (H(2)O(2)) induced an increase in the AGT expression in primary rat mesangial cells. Furthermore, the H(2)O(2)-induced upregulation of AGT was inhibited by a mitogen-activated protein kinase kinase and a c-Jun N-terminal kinase inhibitor. These data suggest the potential contribution of enhanced AGT expression in glomeruli to the intrarenal RAS activation for the development of glomerular disease.