Albumin-induced apoptosis of tubular cells is modulated by BASP1

Albuminuria promotes tubular injury and cell death, and is associated with faster progression of chronic kidney disease (CKD) to end-stage renal disease. However, the molecular mechanisms regulating tubular cell death in response to albuminuria are not fully understood. Brain abundant signal protein 1 (BASP1) was recently shown to mediate glucose-induced apoptosis in tubular cells. We have studied the role of BASP1 in albumin-induced tubular cell death. BASP1 expression was studied in experimental puromycin aminonucleoside-induced nephrotic syndrome in rats and in human nephrotic syndrome. The role of BASP1 in albumin-induced apoptosis was studied in cultured human HK2 proximal tubular epithelial cells. Puromycin aminonucleoside induced proteinuria and increased total kidney BASP1 mRNA and protein expression. Immunohistochemistry localized the increased BASP1 to tubular cells. BASP1 expression colocalized with deoxynucleotidyl-transferase-mediated dUTP nick-end labeling staining for apoptotic cells. Increased tubular BASP1 expression was observed in human proteinuric nephropathy by immunohistochemistry, providing evidence for potential clinical relevance. In cultured tubular cells, albumin induced apoptosis and increased BASP1 mRNA and protein expression at 6–48 h. Confocal microscopy localized the increased BASP1 expression in albumin-treated cells mainly to the perinuclear area. A peripheral location near the cell membrane was more conspicuous in albumin-treated apoptotic cells, where it colocalized with actin. Inhibition of BASP1 expression by a BASP1 siRNA protected from albumin-induced apoptosis. In conclusion, albumin-induced apoptosis in tubular cells is BASP1-dependent. This information may be used to design novel therapeutic approaches to slow CKD progression based on protection of tubular cells from the adverse consequences of albuminuriaGrant support: FIS PS09/00447, PI13/00047, CP14/ 00133, ISCIII-RETIC, REDinREN/RD06/0016/and RD012/0021 FEDER funds, Comunidad de Madrid/CIFRA S2010/BMD-2378. Salary support: FIS to MDSN and ABS (Miguel Servet), Beatriz Fernandez-Fernandez (Rio Hortega). Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to AO. IIS-FJD Biobank RD09/0076/0010

Effective nephroprotection against acute kidney injury with a star-shaped polyglutamate-curcuminoid conjugate

The lack of efective pharmacological treatments for acute kidney injury (AKI) remains a signifcant public health problem. Given the involvement of apoptosis and regulated necrosis in the initiation and progression of AKI, the inhibition of cell death may contribute to AKI prevention/recovery. Curcuminoids are a family of plant polyphenols that exhibit attractive biological properties that make them potentially suitable for AKI treatment. Now, in cultured tubular cells, we demonstrated that a crosslinked self-assembled star-shaped polyglutamate (PGA) conjugate of bisdemethoxycurcumin (StPGA-CL-BDMC) inhibits apoptosis and necroptosis induced by Tweak/TNFα/IFNγ alone or concomitant to caspase inhibition. St-PGA-CL-BDMC also reduced NF-κB activation and subsequent gene transcription. In vivo, St-PGA-CL-BDMC prevented renal cell loss and preserved renal function in mice with folic acid-induced AKI. Mechanistically, St-PGA-CL-BDMC inhibited AKI-induced apoptosis and expression of ferroptosis markers and also decreased the kidney expression of genes involved in tubular damage and infammation, while preserving the kidney expression of the protective factor, Klotho. Thus, due to renal accumulation and attractive pharmacological properties, the application of PGAbased therapeutics may improve nephroprotective properties of current AKI treatmentsTis work was supported by grants from the Instituto de Salud Carlos III, FEDER funds: PI16/02057, PI16/01900, PI18/01133, PI19/00815, ISCIII RETIC REDINREN RD16/0009; Sociedad Española de Nefrología; FRIAT; Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM; ERA-PerMed-JTC2018 (AC18/00071; DTS18/00032); Spanish Ministry of Economy and Competitiveness (Grant numbers SAF2013-44848-R, SAF2016-80427-R). Partly co-funded by FEDER (PO FEDER Valencian Community - 2014–2020

Non-Hermitian SUSY Hydrogen-like Hamiltonians with real spectra

It is shown that the radial part of the Hydrogen Hamiltonian factorizes as the product of two not mutually adjoint first order differential operators plus a complex constant epsilon. The 1-susy approach is used to construct non-hermitian Hamiltonians with hydrogen spectra. Other non-hermitian Hamiltonians are shown to admit an extra `complex energy' at epsilon. New self-adjoint hydrogen-like Hamiltonians are also derived by using a 2-susy transformation with complex conjugate pairs epsilon, (c.c) epsilon.Comment: LaTeX2e file, 13 pages, 6 EPS figures. New references added. The present is a reorganized and simplified versio

Quadratic pseudosupersymmetry in two-level systems

Using the intertwining relation we construct a pseudosuperpartner for a (non-Hermitian) Dirac-like Hamiltonian describing a two-level system interacting in the rotating wave approximation with the electric component of an electromagnetic field. The two pseudosuperpartners and pseudosupersymmetry generators close a quadratic pseudosuperalgebra. A class of time dependent electric fields for which the equation of motion for a two level system placed in this field can be solved exactly is obtained. New interesting phenomenon is observed. There exists such a time-dependent detuning of the field frequency from the resonance value that the probability to populate the excited level ceases to oscillate and becomes a monotonically growing function of time tending to 3/4. It is shown that near this fixed excitation regime the probability exhibits two kinds of oscillations. The oscillations with a small amplitude and a frequency close to the Rabi frequency (fast oscillations) take place at the background of the ones with a big amplitude and a small frequency (slow oscillations). During the period of slow oscillations the minimal value of the probability to populate the excited level may exceed 1/2 suggesting for an ensemble of such two-level atoms the possibility to acquire the inverse population and exhibit lasing properties.Comment: 5 figure

Nonlinear Supersymmetric Quantum Mechanics: concepts and realizations

Nonlinear SUSY approach to preparation of quantum systems with pre-planned spectral properties is reviewed. Possible multidimensional extensions of Nonlinear SUSY are described. The full classification of ladder-reducible and irreducible chains of SUSY algebras in one-dimensional QM is given. Emergence of hidden symmetries and spectrum generating algebras is elucidated in the context of Nonlinear SUSY in one- and two-dimensional QM.Comment: 75 pages, Minor corrections, Version published in Journal of Physics

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Osteoporosis management in hematologic stem cell transplant recipients: Executive summary

Background: Treatment advances have reduced the adverse events associated with hematopoietic stem cell transplant (HSCT) and led to an increased number of transplants performed. HSCT patients are living longer with concerns on long-term outcomes. Bone fragility and fracture are at the forefront for long-term morbidities post-HSCT. Results: In HSCT recipients, evidence has accumulated to support recommendations for more extensive monitoring of bone fragility and more appropriate administration of osteoporosis pharmacotherapies for patients at high risk of bone loss and/or fracture. Conclusion: This executive summary reports and summarizes the main recommendations published previously, including bone assessment, dietary and lifestyle recommendations and osteoporosis medication

PGC-1α deficiency causes spontaneous kidney inflammation and increases the severity of nephrotoxic AKI

PGC‐1α (peroxisome proliferator‐activated receptor gamma coactivator‐1α, PPARGC1A) regulates the expression of genes involved in energy homeostasis and mitochondrial biogenesis. Here we identify inactivation of the transcriptional regulator PGC‐1α as a landmark for experimental nephrotoxic acute kidney injury (AKI) and describe the in vivo consequences of PGC‐1α deficiency over inflammation and cell death in kidney injury. Kidney transcriptomic analyses of WT mice with folic acid‐induced AKI revealed 1398 up‐ and 1627 downregulated genes. Upstream transcriptional regulator analyses pointed to PGC‐1α as the transcription factor potentially driving the observed expression changes with the highest reduction in activity. Reduced PGC‐1α expression was shared by human kidney injury. Ppargc1a−/− mice had spontaneous subclinical kidney injury characterized by tubulointerstitial inflammation and increased Ngal expression. Upon AKI, Ppargc1a−/− mice had lower survival and more severe loss of renal function, tubular injury, and reduction in expression of mitochondrial PGC‐1α‐dependent genes in the kidney, and an earlier decrease in mitochondrial mass than WT mice. Additionally, surviving Ppargc1a−/− mice showed higher rates of tubular cell death, compensatory proliferation, expression of proinflammatory cytokines, NF‐κB activation, and interstitial inflammatory cell infiltration. Specifically, Ppargc1a−/− mice displayed increased M1 and decreased M2 responses and expression of the anti‐inflammatory cytokine IL‐10. In cultured renal tubular cells, PGC‐1α targeting promoted spontaneous cell death and proinflammatory responses. In conclusion, PGC‐1α inactivation is a key driver of the gene expression response in nephrotoxic AKI and PGC‐1α deficiency promotes a spontaneous inflammatory kidney response that is magnified during AKI.Sandra Zazo and Federico Rojo of the IIS‐FJD Biobank (B.0000647). FIS/Fondos FEDER (PI15/00298, CP14/00133, PI16/02057, PI16/01900, ISCIII‐RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD‐3686 CIFRA2‐CM. Grants from the Spanish ‘Ministerio de Economía Industria y Competitividad’ (MINEICO) and FEDER funds (Grant numbers SAF2015‐63904‐R, SAF2015‐71521‐REDC), and from the EC H2020 framework program Grant MSCA‐ITN‐2016‐721236 to MM. Salary support: ISCIII Miguel Servet and to ABS and MDS‐N. ISCIII Sara Borrell to JM‐MM, and Fundación Conchita Rabago to DMS. Consejería de Educación, Juventud y Deporte (Comunidad de Madrid/FSE) to MF‐B.Peer reviewe