Performances of acute kidney injury biomarkers vary according to sex.

Background: Before implementing individualized strategies to treat acute kidney injury (AKI), identifying clusters of patients with divergent pathophysiological mechanisms, diagnosis criteria or outcomes is of the utmost importance. Here we studied sex-related molecular mechanisms in cardiac bypass (CBP) surgery patients developing AKI. Methods: We compared the characteristics of 1170 patients referred for CBP surgery using multivariate logistic regression and propensity score-based analysis. Performances of the candidate urinary biomarkers at <4 h post-surgery, urinary neutrophil gelatinase-associated lipocalin (uNGAL), [IGFBP7]·[TIMP-2] product (NephroCheck) and a recently developed AKI signature of 204 urinary peptides (AKI204) to predict AKI were compared in both sexes. Results: Incidence (∼25%) and severity of AKI were similar in men and women, even after adjustment for the usual risk factors of AKI, including baseline estimated glomerular filtration rate, age, diabetes mellitus, length of CBP and red blood cell transfusion. However, at the molecular level, performances of uNGAL, NephroCheck and AKI204 to predict AKI strongly diverged between men and women. In the full cohort, as well as in subgroups of men and women, the multimarker AKI204 signature outperformed uNGAL and NephroCheck and predicted the development of AKI significantly better in women than in men. Analysis of AKI204 at the single-peptide level suggested divergences of AKI mechanisms between sexes due to increased kidney inflammation in women (increased abundance of urinary fragments of osteopontin and uromodulin). Conclusions: In patients referred for CBP surgery, significant clinical and biological differences between men and women as well as sexual dimorphism of AKI biomarker performances were identified. The urinary peptide signature points to sex-related molecular mechanisms underlying AKI.

mRNA Decapping Activator Pat1 Is Required for Efficient Yeast Adaptive Transcriptional Responses via the Cell Wall Integrity MAPK Pathway.

Cellular mRNA levels, particularly under stress conditions, can be finely regulated by the coordinated action of transcription and degradation processes. Elements of the 5'-3' mRNA degradation pathway, functionally associated with the exonuclease Xrn1, can bind to nuclear chromatin and modulate gene transcription. Within this group are the so-called decapping activators, including Pat1, Dhh1, and Lsm1. In this work, we have investigated the role of Pat1 in the yeast adaptive transcriptional response to cell wall stress. Thus, we demonstrated that in the absence of Pat1, the transcriptional induction of genes regulated by the Cell Wall Integrity MAPK pathway was significantly affected, with no effect on the stability of these transcripts. Furthermore, under cell wall stress conditions, Pat1 is recruited to Cell Wall Integrity-responsive genes in parallel with the RNA Pol II complex, participating both in pre-initiation complex assembly and transcriptional elongation. Indeed, strains lacking Pat1 showed lower recruitment of the transcription factor Rlm1, less histone H3 displacement at Cell Wall Integrity gene promoters, and impaired recruitment and progression of RNA Pol II. Moreover, Pat1 and the MAPK Slt2 occupied the coding regions interdependently. Our results support the idea that Pat1 and presumably other decay factors behave as transcriptional regulators of Cell Wall Integrity-responsive genes under cell wall stress conditions.

Urine MMP7 as a kidney injury biomarker.

Matrix metalloproteinase 7 (MMP-7) is a secreted endopeptidase involved in the degradation of extracellular matrix components and the activation of cytokines and growth factors. The regulation of MMP-7 can be transcriptionally regulated by AP-1 or Wnt/ß-catenin or post-translationally by proteolytic activation. MMP-7 expression is low or absent in the healthy kidney, but is significantly upregulated in kidney injury, including AKI and CKD. The function of MMP-7 in kidney disease may differ for CKD and AKI; it may have a profibrotic role in CKD and an anti-apoptotic and regenerative function in AKI. Additionally, the potential of MMP-7 as a biomarker has been studied in different kidney diseases, and the results are promising. Recently, combined unbiased kidney proteomics and transcriptomics approaches identified kidney MMP-7 as the protein having the strongest association with both fibrosis and eGFR and confirmed the predictive role of plasma MMP-7 levels for kidney function decline in over 11 000 individuals. Additionally, urinary MMP-7, combined with urinary cystatin C (CysC) and retinol binding protein (RBP) was reported to provide information on tubular injury in focal segmental glomerulosclerosis and minimal change disease. We now present an overview of research on MMP-7 expression and function in kidney diseases and discuss its potential as a biomarker of kidney diseases.

NephroCheck at 10: addressing unmet needs in AKI diagnosis and risk stratification.

Despite its name, the current diagnosis of acute kidney injury (AKI) still depends on markers of decreased kidney function and not on markers of injury. This results in a delayed diagnosis: AKI is diagnosed based on serum creatinine criteria only when the severity of injury is enough to decrease glomerular filtration rate. Moreover, by the time AKI is diagnosed, the insult may have already ceased, and even appropriate therapy targeted at the specific insult and its associated pathogenic pathways may no longer be effective. Biomarkers of injury are needed that allow the diagnosis of AKI based on injury criteria. At least three commercially available immunoassays assessing urinary or plasma neutrophil gelatinase-associated lipocalin and urinary tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein-7 ([TIMP2]*[IGFBP7]) (NephroCheck®) have generated promising data regarding prediction and early diagnosis of AKI, although their relative performance may depend on clinical context. Recently, a urinary peptidomics classifier (PeptAKI) was reported to predict AKI better than current biomarkers. Focusing on [TIMP2]*[IGFBP7], the cellular origin of urinary TIMP2 and IGFBP7 remains unclear, especially under the most common predisposing condition for AKI, i.e. chronic kidney disease. We now discuss novel data on the kidney cell expression of TIMP2 and IGFBP7 and its clinical implications.

Targeting the TWEAK-Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury.

Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+ ) handling alterations. Next, we investigated the role of the TWEAK-Fn14 axis in cardiomyocyte function following renal ischaemia-reperfusion (I/R) injury in mice. We observed that TWEAK-Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+ -adenosine triphosphatase 2a pump (SERCA2a ) and ryanodine receptor (RyR2 ) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK-Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Dynamics of urine proteomics biomarker and disease progression in patients with IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) frequently leads to kidney failure. The urinary proteomics-based classifier IgAN237 may predict disease progression at the time of kidney biopsy. We studied whether IgAN237 also predicts progression later in the course of IgAN. METHODS: Urine from patients with biopsy-proven IgAN was analyzed using capillary electrophoresis-mass spectrometry at baseline (IgAN237-1, n = 103) and at follow-up (IgAN237-2, n = 89). Patients were categorized as "non-progressors" (IgAN237 ≤0.38) and "progressors" (IgAN237 >0.38). Estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio slopes were calculated. RESULTS: Median age at biopsy was 44 years, interval between biopsy and IgAN237-1 was 65 months and interval between IgAN237-1 and IgAN237-2 was 258 days (interquartile range 71-531). IgAN237-1 and IgAN237-2 values did not differ significantly and were correlated (rho = 0.44, P < .001). Twenty-eight percent and 26% of patients were progressors based on IgAN237-1 and IgAN237-2, respectively. IgAN237 inversely correlated with chronic eGFR slopes (rho = -0.278, P = .02 for score-1; rho = -0.409, P = .002 for score-2) and with ±180 days eGFR slopes (rho = -0.31, P = .009 and rho = -0.439, P = .001, respectively). The ±180 days eGFR slopes were worse for progressors than for non-progressors (median -5.98 versus -1.22 mL/min/1.73 m2 per year for IgAN237-1, P < .001; -3.02 vs 1.08 mL/min/1.73 m2 per year for IgAN237-2, P = .0047). In multiple regression analysis baseline progressor/non-progressor according to IgAN237 was an independent predictor of eGFR180days-slope (P = .001). CONCLUSION: The urinary IgAN237 classifier represents a risk stratification tool in IgAN also later in the course of the dynamic disease. It may guide patient management in an individualized manner.

Systematic Identification of Essential Genes Required for Yeast Cell Wall Integrity: Involvement of the RSC Remodelling Complex.

Conditions altering the yeast cell wall lead to the activation of an adaptive transcriptional response mainly governed by the cell wall integrity (CWI) mitogen-activated protein kinase (MAPK) pathway. Two high-throughput screenings were developed using the yTHC collection of yeast conditional mutant strains to systematically identify essential genes related to cell wall integrity, and those required for the transcriptional program elicited by cell wall stress. Depleted expression of 52 essential genes resulted in hypersensitivity to the dye Calcofluor white, with chromatin organization, Golgi vesicle transport, rRNA processing, and protein glycosylation processes, as the most highly representative functional groups. Via a flow cytometry-based quantitative assay using a CWI reporter plasmid, 97 strains exhibiting reduced gene-reporter expression levels upon stress were uncovered, highlighting genes associated with RNA metabolism, transcription/translation, protein degradation, and chromatin organization. This screening also led to the discovery of 41 strains displaying a basal increase in CWI-associated gene expression, including mainly putative cell wall-related genes. Interestingly, several members of the RSC chromatin remodelling complex were uncovered in both screenings. Notably, Rsc9 was necessary to regulate the gene expression of CWI-related genes both under stress and non-stress conditions, suggesting distinct requirements of the RSC complex for remodelling particular genes.

Control of Gene Expression via the Yeast CWI Pathway.

Living cells exposed to stressful environmental situations can elicit cellular responses that guarantee maximal cell survival. Most of these responses are mediated by mitogen-activated protein kinase (MAPK) cascades, which are highly conserved from yeast to humans. Cell wall damage conditions in the yeast Saccharomyces cerevisiae elicit rescue mechanisms mainly associated with reprogramming specific transcriptional responses via the cell wall integrity (CWI) pathway. Regulation of gene expression by this pathway is coordinated by the MAPK Slt2/Mpk1, mainly via Rlm1 and, to a lesser extent, through SBF (Swi4/Swi6) transcription factors. In this review, we summarize the molecular mechanisms controlling gene expression upon cell wall stress and the role of chromatin structure in these processes. Some of these mechanisms are also discussed in the context of other stresses governed by different yeast MAPK pathways. Slt2 regulates both transcriptional initiation and elongation by interacting with chromatin at the promoter and coding regions of CWI-responsive genes but using different mechanisms for Rlm1- and SBF-dependent genes. Since MAPK pathways are very well conserved in eukaryotic cells and are essential for controlling cellular physiology, improving our knowledge regarding how they regulate gene expression could impact the future identification of novel targets for therapeutic intervention.

Nicotinamide and acute kidney injury.

In a recent issue of ckj, Piedrafita et al. reported that urine tryptophan and kynurenine are reduced in cardiac bypass surgery patients that develop acute kidney injury (AKI), suggesting reduced activity of the kynurenine pathway of nicotinamide (NAM) adenine dinucleotide (NAD+) synthesis from tryptophan. However, NAM supplementation aiming at repleting NAD+ did not replete kidney NAD+ and did not improve glomerular filtration or reduce histological injury in ischaemic-reperfusion kidney injury in mice. The lack of improvement of kidney injury is partially at odds with prior reports that did not study kidney NAD+, glomerular filtration or histology in NAM-treated wild-type mice with AKI. We now present an overview of research on therapy with vitamin B3 vitamers and derivate molecules {niacin, Nicotinamide [NAM; niacinamide], NAM riboside [Nicotinamide riboside (NR)], Reduced nicotinamide riboside [NRH] and NAM mononucleotide} in kidney injury, including an overview of ongoing clinical trials, and discuss the potential explanations for diverging reports on the impact of these therapeutic approaches on pre-clinical acute and chronic kidney disease.

Poacic acid, a ß-1,3-glucan-binding antifungal agent, inhibits cell-wall remodeling and activates transcriptional responses regulated by the cell-wall integrity and high-osmolarity glycerol pathways in yeast.

As a result of the relatively few available antifungals and the increasing frequency of resistance to them, the development of novel antifungals is increasingly important. The plant natural product poacic acid (PA) inhibits ß-1,3-glucan synthesis in Saccharomyces cerevisiae and has antifungal activity against a wide range of plant pathogens. However, the mode of action of PA is unclear. Here, we reveal that PA specifically binds to ß-1,3-glucan, its affinity for which is ~30-fold that for chitin. Besides its effect on ß-1,3-glucan synthase activity, PA inhibited the yeast glucan-elongating activity of Gas1 and Gas2 and the chitin-glucan transglycosylase activity of Crh1. Regarding the cellular response to PA, transcriptional co-regulation was mediated by parallel activation of the cell-wall integrity (CWI) and high-osmolarity glycerol signaling pathways. Despite targeting ß-1,3-glucan remodeling, the transcriptional profiles and regulatory circuits activated by caspofungin, zymolyase, and PA differed, indicating that their effects on CWI have different mechanisms. The effects of PA on the growth of yeast strains indicated that it has a mode of action distinct from that of echinocandins, suggesting it is a unique antifungal agent.

Role of Macrophages and Related Cytokines in Kidney Disease.

Inflammation is a key characteristic of kidney disease, but this immune response is two-faced. In the acute phase of kidney injury, there is an activation of the immune cells to fight against the insult, contributing to kidney repair and regeneration. However, in chronic kidney diseases (CKD), immune cells that infiltrate the kidney play a deleterious role, actively participating in disease progression, and contributing to nephron loss and fibrosis. Importantly, CKD is a chronic inflammatory disease. In early CKD stages, patients present sub-clinical inflammation, activation of immune circulating cells and therefore, anti-inflammatory strategies have been proposed as a common therapeutic target for renal diseases. Recent studies have highlighted the plasticity of immune cells and the complexity of their functions. Among immune cells, monocytes/macrophages play an important role in all steps of kidney injury. However, the phenotype characterization between human and mice immune cells showed different markers; therefore the extrapolation of experimental studies in mice could not reflect human renal diseases. Here we will review the current information about the characteristics of different macrophage phenotypes, mainly focused on macrophage-related cytokines, with special attention to the chemokine CCL18, and its murine functional homolog CCL8, and the macrophage marker CD163, and their role in kidney pathology.

Urinary Growth Differentiation Factor-15 (GDF15) levels as a biomarker of adverse outcomes and biopsy findings in chronic kidney disease.

BACKGROUND: Growth Differentiation Factor-15 (GDF15) is a member of the TGF-ß superfamily. Increased serum GDF15 has been associated with increased risk of chronic kidney disease (CKD) progression. However, no prior studies have addressed the significance of urinary GDF15 in adult CKD. METHODS: We measured serum and urinary GDF15 in a prospective cohort of 84 patients who underwent kidney biopsy and assessed their association with outcomes (survival, kidney replacement therapy) during a follow-up of 29 ± 17 months. RESULTS: There was a statistically significant correlation between serum and urine GDF15 values. However, while serum GDF15 values increased with decreasing glomerular filtration rate, urinary GDF15 did not. Immunohistochemistry located kidney GDF15 expression mainly in tubular cells, and kidney GDF15 staining correlated with urinary GDF15 values. Urine GDF15 was significantly higher in patients with a histologic diagnosis of diabetic nephropathy than in diabetic patients without diabetic nephropathy. This was not the case for serum GDF15. Both serum and urine GDF15 were negatively associated with patient survival in multivariate models. However, when both urine and serum GDF15 were present in the model, lower urine GDF15 predicted patient survival [B coefficient (SEM) - 0.395 (0.182) p 0.03], and higher urine GDF15 predicted a composite of mortality or kidney replacement therapy [0.191 (0.06) p 0.002], while serum GDF15 was not predictive. Decision tree analysis yielded similar results. The area under the curve (AUC) of the receiver operating curve (ROC) for urine GDF15 as a predictor of mortality was 0.95 (95% CI 0.89-1.00, p < 0.001). CONCLUSIONS: In conclusion, urinary GDF15 is associated with kidney histology patterns, mortality and the need for renal replacement therapy (RRT) in CKD patients who underwent a kidney biopsy.

The Botrytis cinerea Crh1 transglycosylase is a cytoplasmic effector triggering plant cell death and defense response.

Crh proteins catalyze crosslinking of chitin and glucan polymers in fungal cell walls. Here, we show that the BcCrh1 protein from the phytopathogenic fungus Botrytis cinerea acts as a cytoplasmic effector and elicitor of plant defense. BcCrh1 is localized in vacuoles and the endoplasmic reticulum during saprophytic growth. However, upon plant infection, the protein accumulates in infection cushions; it is then secreted to the apoplast and translocated into plant cells, where it induces cell death and defense responses. Two regions of 53 and 35 amino acids are sufficient for protein uptake and cell death induction, respectively. BcCrh1 mutant variants that are unable to dimerize lack transglycosylation activity, but are still able to induce plant cell death. Furthermore, Arabidopsis lines expressing the bccrh1 gene exhibit reduced sensitivity to B. cinerea, suggesting a potential use of the BcCrh1 protein in plant immunization against this necrotrophic pathogen.

Urine proteomics for prediction of disease progression in patients with IgA nephropathy.

BACKGROUND: Risk of kidney function decline in immunoglobulin A (IgA) nephropathy (IgAN) is significant and may not be predicted by available clinical and histological tools. To serve this unmet need, we aimed at developing a urinary biomarker-based algorithm that predicts rapid disease progression in IgAN, thus enabling a personalized risk stratification. METHODS: In this multicentre study, urine samples were collected in 209 patients with biopsy-proven IgAN. Progression was defined by tertiles of the annual change of estimated glomerular filtration rate (eGFR) during follow-up. Urine samples were analysed using capillary electrophoresis coupled mass spectrometry. The area under the receiver operating characteristic curve (AUC) was used to evaluate the risk prediction models. RESULTS: Of the 209 patients, 64% were male. Mean age was 42 years, mean eGFR was 63 mL/min/1.73 m2 and median proteinuria was 1.2 g/day. We identified 237 urine peptides showing significant difference in abundance according to the tertile of eGFR change. These included fragments of apolipoprotein C-III, alpha-1 antitrypsin, different collagens, fibrinogen alpha and beta, titin, haemoglobin subunits, sodium/potassium-transporting ATPase subunit gamma, uromodulin, mucin-2, fractalkine, polymeric Ig receptor and insulin. An algorithm based on these protein fragments (IgAN237) showed a significant added value for the prediction of IgAN progression [AUC 0.89; 95% confidence interval (CI) 0.83-0.95], as compared with the clinical parameters (age, gender, proteinuria, eGFR and mean arterial pressure) alone (0.72; 95% CI 0.64-0.81). CONCLUSIONS: A urinary peptide classifier predicts progressive loss of kidney function in patients with IgAN significantly better than clinical parameters alone.

Tacrolimus Prevents TWEAK-Induced PLA2R Expression in Cultured Human Podocytes.

Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NFκB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawal.

TRAF3 Modulation: Novel Mechanism for the Anti-inflammatory Effects of the Vitamin D Receptor Agonist Paricalcitol in Renal Disease.

BACKGROUND: CKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of action are poorly understood. METHODS: Modulation of the noncanonical NF-κB2 pathway and its component TNF receptor-associated factor 3 (TRAF3) by the VDRA paricalcitol was studied in PBMCs from patients with ESKD, cytokine-stimulated cells, and preclinical kidney injury models. RESULTS: In PBMCs isolated from patients with ESKD, TRAF3 protein levels were lower than in healthy controls. This finding was associated with evidence of noncanonical NF-κB2 activation and a proinflammatory state. However, PBMCs from patients with ESKD treated with paricalcitol did not exhibit these features. Experiments in cultured cells confirmed the link between TRAF3 and NF-κB2/inflammation. Decreased TRAF3 ubiquitination in K48-linked chains and cIAP1-TRAF3 interaction mediated the mechanisms of paricalcitol action.TRAF3 overexpression by CRISPR/Cas9 technology mimicked VDRA's effects. In a preclinical model of kidney injury, paricalcitol inhibited renal NF-κB2 activation and decreased renal inflammation. In VDR knockout mice with renal injury, paricalcitol prevented TRAF3 downregulation and NF-κB2-dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol. CONCLUSIONS: These data suggest the anti-inflammatory actions of paricalcitol depend on TRAF3 modulation and subsequent inhibition of the noncanonical NF-κB2 pathway, identifying a novel mechanism for VDRA's effects. Circulating TRAF3 levels could be a biomarker of renal damage associated with the inflammatory state.

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy.

Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several anti-inflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury.

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases.

: Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

MAP3K kinases and kidney injury / MAP3K quinasas y daño renal

Mitogen-activated protein kinases (MAP kinases) are functionally connected kinases that regulate key cellular process involved in kidney disease such as all survival, death, differentiation and proliferation. The typical MAP kinase module is composed by a cascade of three kinases: a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates a MAP kinase kinase (MAP2K) which phosphorylates a MAP kinase (MAPK). While the role of MAPKs such as ERK, p38 and JNK has been well characterized in experimental kidney injury, much less is known about the apical kinases in the cascade, the MAP3Ks. There are 24 characterized MAP3K (MAP3K1 to MAP3K21 plus RAF1, BRAF and ARAF). We now review current knowledge on the involvement of MAP3K in non-malignant kidney disease and the therapeutic tools available. There is in vivo interventional evidence clearly supporting a role for MAP3K5 (ASK1) and MAP3K14 (NIK) in the pathogenesis of experimental kidney disease. Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease. Additionally, although MAP3K7 (MEKK7, TAK1) is required for kidney development, acutely targeting MAP3K7 protected from acute and chronic kidney injury; and targeting MAP3K8 (TPL2/Cot) protected from acute kidney injury. By contrast MAP3K15 (ASK3) may protect from hypertension and BRAF inhibitors in clinical use may induced acute kidney injury and nephrotic syndrome. Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexplored

Las proteínas quinasas activadas por mitógenos (MAP quinasas) son quinasas conectadas funcionalmente que regulan procesos celulares clave involucrados en la enfermedad renal como la supervivencia, la muerte, la diferenciación y la proliferación. El típico módulo MAP quinasa está compuesto por una cascada de 3 quinasas: una MAP quinasa quinasa quinasa (MAP3K) que fosforila y activa una MAP quinasa quinasa (MAP2K) que, a su vez, fosforila una MAP quinasa (MAPK). Si bien el papel de las MAPK como ERK, p38 y JNK se ha caracterizado bien en las lesiones renales experimentales, se sabe mucho menos acerca de las quinasas apicales en la cascada, las MAP3K. Hay 24 MAP3K (MAP3K1 a MAP3K21, más RAF1, BRAF y ARAF). En este trabajo revisamos el conocimiento actual sobre la participación de MAP3K en la enfermedad renal no maligna y las herramientas terapéuticas disponibles. Existe evidencia intervencionista experimental in vivo que respalda claramente el papel de MAP3K5 (ASK1) y MAP3K14 (NIK) en la patogenia de la enfermedad renal experimental. De hecho, el inhibidor de ASK1, selonsertib, ha sido estudiado en ensayos clínicos en la enfermedad renal diabética. Además, aunque la MAP3K7 (MEKK7, TAK1) es necesaria para el desarrollo renal, la inhibición de MAP3K7 en el adulto protegió de la lesión renal aguda y crónica experimental; e inhibir MAP3K8 (TPL2/Cot) protegió de la lesión renal aguda. Por el contrario, MAP3K15 (ASK3) puede proteger de la hipertensión y los inhibidores de BRAF, en uso clínico, pueden inducir lesión renal aguda y síndrome nefrótico. Dado su papel como reguladores de los primeros pasos de la señalización intracelular, las MAP3K son posibles dianas terapéuticas en la lesión renal, como se ha demostrado para algunas de ellos. Sin embargo, el papel de la mayoría de las MAP3K en la enfermedad renal no ha sido explorado

Dietary Care for ADPKD Patients: Current Status and Future Directions.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic nephropathy, and tolvaptan is the only therapy available. However, tolvaptan slows but does not stop disease progression, is marred by polyuria, and most patients worldwide lack access. This and recent preclinical research findings on the glucose-dependency of cyst-lining cells have renewed interest in the dietary management of ADPKD. We now review the current dietary recommendations for ADPKD patients according to clinical guidelines, the evidence base for those, and the potential impact of preclinical studies addressing the impact of diet on ADPKD progression. The clinical efficacy of tolvaptan has put the focus on water intake and solute ingestion as modifiable factors that may impact tolvaptan tolerance and ADPKD progression. By contrast, dietary modifications suggested to ADPKD patients, such as avoiding caffeine, are not well supported and their impact is unknown. Recent studies have identified a chronic shift in energy production from mitochondrial oxidative phosphorylation to aerobic glycolysis (Warburg effect) as a contributor to cyst growth, rendering cyst cells exquisitely sensitive to glucose availability. Therefore, low calorie or ketogenic diets have delayed preclinical ADPKD progression. Additional preclinical data warn of potential negative impact of excess dietary phosphate or oxalate in ADPKD progression.