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The strong predictive value of proteinuria in chronic glomerulopathies is firmly established as well as the pathogenic role of angiotensin II promoting progression of glomerular disease with an altered glomerular filtration barrier, podocyte injury and scarring of glomeruli. Here we found that chronic angiotensin II-induced hypertension inhibited autophagy flux in mouse glomeruli. Deletion of Atg5 (a gene encoding a protein involved autophagy) specifically in the podocyte resulted in accelerated angiotensin II-induced podocytopathy, accentuated albuminuria and glomerulosclerosis. This indicates that autophagy is a key protective mechanism in the podocyte in this condition. Angiotensin-II induced calpain activity in podocytes inhibits autophagy flux. Podocytes from mice with transgenic expression of the endogenous calpain inhibitor calpastatin displayed higher podocyte autophagy at baseline that was resistant to angiotensin II-dependent inhibition. Also, sustained autophagy with calpastatin limited podocyte damage and albuminuria. These findings suggest that hypertension has pathogenic effects on the glomerular structure and function, in part through activation of calpains leading to blockade of podocyte autophagy. These findings uncover an original mechanism whereby angiotensin II-mediated hypertension inhibits autophagy via calcium-induced recruitment of calpain with pathogenic consequences in case of imbalance by calpastatin activity. Thus, preventing a calpain-mediated decrease in autophagy may be a promising new therapeutic strategy for nephropathies associated with high renin-angiotensin system activity., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis., Methods: We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN)., Results: Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P < 0.0001 for all comparisons) than MCNS patients in remission. Plasmablasts were the only B-cell subsets present at significantly higher levels in MCNS-Rel patients than in the patients of the other three groups (P < 0.05 for all comparisons). The lower albumin levels and higher proteinuria levels were positively correlated with the percentage of circulating plasmablasts (Spearman test's ρ = -0.54, P = 0.01 and ρ = 0.65, P = 0.002, respectively). Similarly, the increase of immunoglobulin M (IgM) and the decrease of IgG levels were significantly associated with the percentage of plasmablasts in MCNS-Rel patients (Spearman's ρ = 0.36, P = 0.01 and Spearman's ρ = -0.60, P = 0.01, respectively). Increased production of interleukin (IL)-21, IL-6 and B-cell activating factor (BAFF) in the serum of MCNS-Rel patients was found significantly correlated with the percentage of plasmablasts (ρ = 0.72, P = 0.0002, ρ = 0.49, P = 0.04 and ρ = 0.62, P = 0.009, respectively)., Conclusions: An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

"Targeted therapies and pathophysiological mechanisms of proteinuria Targeted therapy represents a promising therapeutic approach for patients with diverse cancers and has enabled significant development in medical oncology. This new class of anticancer drugs includes antibodies, fusion-proteins and receptor tyrosine kinase inhibitors among others. Depending on their molecular targeting, side effects can affect multiple organs, especially the kidney. Antiangiogenic agents inhibit the VEGF/VEGFR pathway resulting in reduction of nitric oxide production and alteration of podocytes function, which causes hypertension and proteinuria. EGFR inhibitors are responsible of electrolytic disorders. Hereby, we synthetized the current knowledge on renal toxicities on main molecular targeted therapies. Toxicities management is mainly based on clinical and biological monitoring, which can lead to drug withdrawing or dose adaptation.", Competing Interests: "A. Rousseau, L. Campedel, M.-C. Lafargue, C. Hénique, D. Sahali, C. Isnard-Bagnis déclarent n’avoir aucun lien d’intérêts.P. Gougis déclare avoir été pris en charge lors de congrès par Pfizer."

Systemic lupus erythematosus (SLE) is characterized by a broad spectrum of renal lesions. In lupus glomerulonephritis, histological classifications are based on immune-complex (IC) deposits and hypercellularity lesions (mesangial and/or endocapillary) in the glomeruli. However, there is compelling evidence to suggest that glomerular epithelial cells, and podocytes in particular, are also involved in glomerular injury in patients with SLE. Podocytes now appear to be not only subject to collateral damage due to glomerular capillary lesions secondary to IC and inflammatory processes, but they are also a potential direct target in lupus nephritis. Improvements in our understanding of podocyte injury could improve the classification of lupus glomerulonephritis. Indeed, podocyte injury may be prominent in two major presentations: lupus podocytopathy and glomerular crescent formation, in which glomerular parietal epithelial cells play also a key role. We review here the contribution of podocyte impairment to different presentations of lupus nephritis, focusing on the podocyte signaling pathways involved in these lesions.

Necrotizing and crescentic rapidly progressive glomerulonephritis or crescentic glomerulonephritis is one of the severest forms of acquired glomerular diseases with significant mortality. Risk of end-stage renal failure at 5 years is near 30%, with a number of patients developing chronic kidney disease. Currently, autoimmune crescentic glomerulonephritides are treated with broad-spectrum immunosuppression inducing remission of the injury in the majority of patients. However, treatment is associated with significant side effects and by the time remission is achieved the majority of patients have developed renal tissue damage and significant impairment of their kidney function with a steep slope of deterioration within the first weeks following initiation of immunosuppression. It is therefore important to develop complementary strategies that would be immediately active on the common process of destructive epithelial processes. We have worked to identify the major cellular pathways contributing to glomerular destruction in this context by a systematic comparison of patient tissues and experimental models. Our studies demonstrate the pivotal role of local intra- and intercellular communications in orchestrating the global glomerular tolerance to a severe rapidly progressive glomerulonephritis model with excellent anatomoclinical correlative expressions in kidney biopsies of individuals diagnosed with crescentic glomerulonephritis, irrespectively of the causal immune disorder. We hope that such approaches deciphering mechanisms of cellular adaptation that underlie kidney damage control in response to vasculitides, integrating both stress and damage responses, will delineate novel complementary therapies., (Copyright © 2019 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Generation of de novo donor-specific antibodies ( dn DSAs) after renal transplant is recognized as the leading cause of late transplant failure. Hence, the optimal immunosuppressive strategies to limit dn DSA development need to be defined. Recent clinical trials using the novel costimulatory blockade agent CTLA4-Ig (Belatacept) have shown that kidney transplant recipients (KTRs) treated with Belatacept have better graft survival and function and a lower proportion of dn DSAs than control-treated KTRs. Mechanisms involved in the control of humoral responses by Belatacept remain to be investigated. Here, we analyzed the effect of Belatacept on different steps of the B cell-mediated response in humans. In vitro , Belatacept reduced plasmablast differentiation, Ig production, and the expression of the major transcription factor involved in plasma cell function, Blimp-1, in a T cell-independent manner. Moreover, Belatacept induced activation of the STAT3 transcription factor in stimulated B cells and reduced the expression of CD86. Additionally, Belatacept blocked CD28-mediated activation of T follicular helper cells (Tfhs) in an autologous Tfh-memory B cells model. We then validated these observations in KTRs treated with Belatacept, who had a reduced proportion of blood effector B cells and activated Tfh (PD1 + ICOS + ) compared with control-treated KTRs. Our in vitro and in vivo results suggest that Belatacept modulates B cell function directly and at the level of B cell-Tfh interaction. These mechanisms likely account for the optimal control of humoral responses observed in KTRs treated with Belatacept., (Copyright © 2018 by the American Society of Nephrology.)

Background: Innate immune responses activated through myeloid cells contribute to the initiation, progression, and complications of atherosclerosis in experimental models. However, the critical upstream pathways that link innate immune activation to foam cell formation are still poorly identified., Objectives: This study sought to investigate the hypothesis that activation of the triggering receptor expressed on myeloid cells (TREM-1) plays a determinant role in macrophage atherogenic responses., Methods: After genetically invalidating Trem-1 in chimeric Ldlr -/- Trem-1 -/- mice and double knockout ApoE -/- Trem-1 -/- mice, we pharmacologically inhibited Trem-1 using LR12 peptide., Results: Ldlr -/- mice reconstituted with bone marrow deficient for Trem-1 (Trem-1 -/- ) showed a strong reduction of atherosclerotic plaque size in both the aortic sinus and the thoracoabdominal aorta, and were less inflammatory compared to plaques of Trem-1 +/+ chimeric mice. Genetic invalidation of Trem-1 led to alteration of monocyte recruitment into atherosclerotic lesions and inhibited toll-like receptor 4 (TLR 4)-initiated proinflammatory macrophage responses. We identified a critical role for Trem-1 in the upregulation of cluster of differentiation 36 (CD36), thereby promoting the formation of inflammatory foam cells. Genetic invalidation of Trem-1 in ApoE -/- /Trem-1 -/- mice or pharmacological blockade of Trem-1 in ApoE -/- mice using LR-12 peptide also significantly reduced the development of atherosclerosis throughout the vascular tree, and lessened plaque inflammation. TREM-1 was expressed in human atherosclerotic lesions, mainly in lipid-rich areas with significantly higher levels of expression in atheromatous than in fibrous plaques., Conclusions: We identified TREM-1 as a major upstream proatherogenic receptor. We propose that TREM-1 activation orchestrates monocyte/macrophage proinflammatory responses and foam cell formation through coordinated and combined activation of CD36 and TLR4. Blockade of TREM-1 signaling may constitute an attractive novel and double-hit approach for the treatment of atherosclerosis., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Because the protective effect of oleate against palmitate-induced insulin resistance may be lessened in skeletal muscle once cell metabolism is overloaded by fatty acids (FAs), we examined the impact of varying amounts of oleate on palmitate metabolic channeling and insulin signaling in C2C12 myotubes. Cells were exposed to 0.5mM of palmitate and to increasing doses of oleate (0.05, 0.25 and 0.5mM). Impacts of FA treatments on radio-labelled FA fluxes, on cellular content in diacylglycerols (DAG), triacylglycerols (TAG), ceramides, acylcarnitines, on PKCθ, MAPKs (ERK1/2, p38) and NF-ΚB activation, and on insulin-dependent Akt phosphorylation were examined. Low dose of oleate (0.05mM) was sufficient to improve palmitate complete oxidation to CO 2 (+29%, P<0.05) and to alter the cellular acylcarnitine profile. Insulin-induced Akt phosphorylation was 48% higher in that condition vs. palmitate alone (p<0.01). Although DAG and ceramide contents were significantly decreased with 0.05mM of oleate vs. palmitate alone (-47 and -28%, respectively, p<0.01), 0.25mM of oleate was required to decrease p38 MAPK and PKCθ phosphorylation, thus further improving the insulin signaling (+32%, p<0.05). By contrast, increasing oleate concentration from 0.25 to 0.5mM, thus increasing total amount of FA from 0.75 to 1mM, deteriorated the insulin signaling pathway (-30%, p<0.01). This was observed despite low contents in DAG and ceramides, and enhanced palmitate incorporation into TAG (+27%, p<0.05). This was associated with increased incomplete FA β-oxidation and impairment of acylcarnitine profile. In conclusion, these combined data place mitochondrial β-oxidation at the center of the regulation of muscle insulin sensitivity, besides p38 MAPK and PKCθ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Previous studies suggested that microRNA-21 may be upregulated in the liver in non-alcoholic steatohepatitis (NASH), but its role in the development of this disease remains unknown. This study aimed to determine the role of microRNA-21 in NASH., Design: We inhibited or suppressed microRNA-21 in different mouse models of NASH: (a) low-density lipoprotein receptor-deficient ( Ldlr ) mice fed a high-fat diet and treated with antagomir-21 or antagomir control; (b) microRNA-21-deficient and wild-type mice fed a methionine-choline-deficient (MCD) diet; (c) peroxisome proliferation-activator receptor α (PPARα)-deficient mice fed an MCD diet and treated with antagomir-21 or antagomir control. We assessed features of NASH and determined liver microRNA-21 levels and cell localisation. MicroRNA-21 levels were also quantified in the liver of patients with NASH, bland steatosis or normal liver and localisation was determined.-/- ) mice fed a high-fat diet and treated with antagomir-21 or antagomir control; (b) microRNA-21-deficient and wild-type mice fed a methionine-choline-deficient (MCD) diet; (c) peroxisome proliferation-activator receptor α (PPARα)-deficient mice fed an MCD diet and treated with antagomir-21 or antagomir control. We assessed features of NASH and determined liver microRNA-21 levels and cell localisation. MicroRNA-21 levels were also quantified in the liver of patients with NASH, bland steatosis or normal liver and localisation was determined., Results: Inhibiting or suppressing liver microRNA-21 expression reduced liver cell injury, inflammation and fibrogenesis without affecting liver lipid accumulation in Ldlr -/- fed a high-fat diet and in wild-type mice fed an MCD diet. Liver microRNA-21 was overexpressed, primarily in biliary and inflammatory cells, in mouse models as well as in patients with NASH, but not in patients with bland steatosis. PPARα, a known microRNA-21 target, implicated in NASH, was decreased in the liver of mice with NASH and restored following microRNA-21 inhibition or suppression. The effect of antagomir-21 was lost in PPARα-deficient mice., Conclusions: MicroRNA-21 inhibition or suppression decreases liver injury, inflammation and fibrosis, by restoring PPARα expression. Antagomir-21 might be a future therapeutic strategy for NASH., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Adult skeletal muscle is a dynamic, remarkably plastic tissue, which allows myofibers to switch from fast/glycolytic to slow/oxidative types and to increase mitochondrial fatty acid oxidation (mFAO) capacity and vascularization in response to exercise training. mFAO is the main muscle energy source during endurance exercise, with carnitine palmitoyltransferase 1 (CPT1) being the key regulatory enzyme. Whether increasing muscle mFAO affects skeletal muscle physiology in adulthood actually remains unknown. To investigate this, we used in vivo electrotransfer technology to express in mouse tibialis anterior (TA), a fast/glycolytic muscle, a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA, its physiologic inhibitor. In young (2-mo-old) adult mice, muscle CPT1mt expression enhanced mFAO (+40%), but also increased the percentage of oxidative fibers (+28%), glycogen content, and capillary-to-fiber density (+45%). This CPT1mt-induced muscle remodeling, which mimicked exercise-induced oxidative phenotype, led to a greater resistance to muscle fatigue. In the context of aging, characterized by sarcopenia and reduced oxidative capacity, CPT1mt expression in TAs from aged (20-mo-old) mice partially reversed aging-associated sarcopenia and fiber-type transition, and increased muscle capillarity. These findings provide evidence that mFAO regulates muscle phenotype and may be a potential target to combat age-related decline in muscle function., (© FASEB.)

The glomerulus is a highly specialized capillary tuft, which under pressure filters large amounts of water and small solutes into the urinary space, while retaining albumin and large proteins. The glomerular filtration barrier (GFB) is a highly specialized filtration interface between blood and urine that is highly permeable to small and midsized solutes in plasma but relatively impermeable to macromolecules such as albumin. The integrity of the GFB is maintained by molecular interplay between its 3 layers: the glomerular endothelium, the glomerular basement membrane and podocytes, which are highly specialized postmitotic pericytes forming the outer part of the GFB. Abnormalities of glomerular ultrafiltration lead to the loss of proteins in urine and progressive renal insufficiency, underlining the importance of the GFB. Indeed, albuminuria is strongly predictive of the course of chronic nephropathies especially that of diabetic nephropathy (DN), a leading cause of renal insufficiency. We found that high glucose concentrations promote autophagy flux in podocyte cultures and that the abundance of LC3B II in podocytes is high in diabetic mice. Deletion of Atg5 specifically in podocytes resulted in accelerated diabetes-induced podocytopathy with a leaky GFB and glomerulosclerosis. Strikingly, genetic alteration of autophagy on the other side of the GFB involving the endothelial-specific deletion of Atg5 also resulted in capillary rarefaction and accelerated DN. Thus autophagy is a key protective mechanism on both cellular layers of the GFB suggesting autophagy as a promising new therapeutic strategy for DN.

The recent years have seen a number of major progresses in the field of extracapillary glomerulonephritis. This entity is the final damage caused by unrelated immunological disorders such as immune complexes glomerular deposits or microvascular injury caused by proinflammatory cytokines, neutrophil extracellular traps (NET), and cell adhesion molecules in the context of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This review provides a summary of recent advances in the understanding of crescentic glomerulonephritis, focusing on interplays of local immune cells and on local mediators participating to crescent formation especially in anti-glomerular basement membrane (anti-GBM) antibody disease. The recent advances about AAV and lupus nephritis are covered by other chapters of this issue. Nevertheless, these considerations may apply to the general case of crescentic glomerulonephritis of all causes.

The endothelin system has emerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs). We then generated mice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-Cre×Ednra(lox/lox)×Ednrb(lox/lox) [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total β-catenin and phospho-NF-κB expression in wild-type glomeruli, but this effect was attenuated in Pod-ETRKO glomeruli. After streptozotocin injection to induce diabetes, wild-type mice developed mild diabetic nephropathy with microalbuminuria, mesangial matrix expansion, glomerular basement membrane thickening, and podocyte loss, whereas Pod-ETRKO mice presented less albuminuria and were completely protected from glomerulosclerosis and podocyte loss, even when uninephrectomized. Moreover, glomeruli from normal and diabetic Pod-ETRKO mice expressed substantially less total β-catenin and phospho-NF-κB compared with glomeruli from counterpart wild-type mice. This evidence suggests that endothelin-1 drives development of glomerulosclerosis and podocyte loss through direct activation of endothelin receptors and NF-κB and β-catenin pathways in podocytes. Notably, both the expression and function of the ETBR subtype were found to be important. Furthermore, these results indicate that activation of the endothelin-1 pathways selectively in podocytes mediates pathophysiologic crosstalk that influences mesangial architecture and sclerosis., (Copyright © 2014 by the American Society of Nephrology.)

Glomerular kidney diseases are of major public health importance because of their strong impact on the quality of life of patients and of their costly management. A relatively neglected area of study is the local factors that influence development of glomerular demolition. The involvement of a glomerular factor has been now demonstrated in glomerulonephritis with cell proliferation such as crescentic rapidly progressive glomerulonephritis (RPGN). Various unrelated immune disorders promote RPGN, such as antibodies directed against the glomerular basement membrane, deposition of immune complexes or antibodies directed against neutrophils. Despite the heterogeneity of these causing diseases, RPGNs share similar histopathological features, which suggest involvement of common final pathways. De novo expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in glomerular epithelial cells is found specifically in human glomerulonephritis with proliferation of these cells and dedifferentiation of podocytes. A receptor for HB-EGF, the EGF receptor (EGFR), is expressed by parietal epithelial cells and podocytes. Furthermore, in a mouse model of RPGN, HB-EGF deficiency or conditional targeting of the Egfr alleles in podocytes markedly alleviated RPGN, renal failure and death. This indicates that the HB-EGF/EGFR pathway plays a pivotal role in RPGN and opens therapeutic perspectives as EGFR inhibitors are clinically available.