scholarly journals Control of Podocyte and Glomerular Capillary Wall Structure and Elasticity by WNK1 Kinase

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhenan Liu ◽  
Joonho Yoon ◽  
Chonlarat Wichaidit ◽  
Ankita B. Jaykumar ◽  
Hashem A. Dbouk ◽  
...  
Keyword(s):  
Calcineurin Inhibitor ◽  
Traction Force ◽  
Calcineurin Inhibitors ◽  
Wall Structure ◽  
Biophysical Properties ◽  
Glomerular Diseases ◽  
Cytoskeletal Structure ◽  
Wnk Kinases ◽  
Foot Process ◽  
Glomerular Capillaries

Cytoskeletal structure and its regulation are essential for maintenance of the differentiated state of specific types of cells and their adaptation to physiologic and pathophysiologic conditions. Renal glomerular capillaries, composed of podocytes, endothelial cells, and the glomerular basement membrane, have distinct structural and biophysical properties and are the site of injury in many glomerular diseases. Calcineurin inhibitors, immunosuppressant drugs used for organ transplantation and auto-immune diseases, can protect podocytes and glomerular capillaries from injury by preserving podocyte cytoskeletal structure. These drugs cause complications including hypertension and hyperkalemia which are mediated by WNK (With No Lysine) kinases as well as vasculopathy with glomerulopathy. WNK kinases and their target kinases oxidative stress-responsive kinase 1 (OSR1) and SPS1-related proline/alanine-rich kinase (SPAK) have fundamental roles in angiogenesis and are activated by calcineurin inhibitors, but the actions of these agents on kidney vasculature, and glomerular capillaries are not fully understood. We investigated WNK1 expression in cultured podocytes and isolated mouse glomerular capillaries to determine if WNK1 contributes to calcineurin inhibitor-induced preservation of podocyte and glomerular structure. WNK1 and OSR1/SPAK are expressed in podocytes, and in a pattern similar to podocyte synaptopodin in glomerular capillaries. Calcineurin inhibitors increased active OSR1/SPAK in glomerular capillaries, the Young’s modulus (E) of glomeruli, and the F/G actin ratio, effects all blocked by WNK inhibition. In glomeruli, WNK inhibition caused reduced and irregular synaptopodin-staining, abnormal capillary and foot process structures, and increased deformability. In cultured podocytes, FK506 activated OSR1/SPAK, increased lamellipodia, accelerated cell migration, and promoted traction force. These actions of FK506 were reduced by depletion of WNK1. Collectively, these results demonstrate the importance of WNK1 in regulation of the podocyte actin cytoskeleton, biophysical properties of glomerular capillaries, and slit diaphragm structure, all of which are essential to normal kidney function.

Long-Term Effects of the Replacement of Calcineurin Inhibitors With Everolimus and Mycophenolate in Patients With Calcineurin Inhibitor–Related Nephrotoxicity

2020 ◽  
Vol 52 (3) ◽  
pp. 836-842 ◽  
Author(s):  
Mauro Acquaro ◽  
Laura Scelsi ◽  
Carlo Pellegrini ◽  
Alessandra Greco ◽  
Catherine Klersy ◽  
...  
Keyword(s):  
Calcineurin Inhibitor ◽  
Calcineurin Inhibitors ◽  
Long Term Effects

scholarly journals Role of Klotho in Chronic Calcineurin Inhibitor Nephropathy

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Kang Luo ◽  
Sun Woo Lim ◽  
Yi Quan ◽  
Sheng Cui ◽  
Yoo Jin Shin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Aging Process ◽  
Calcineurin Inhibitor ◽  
Calcineurin Inhibitors ◽  
Common Mechanism ◽  
Protective Mechanism ◽  
Klotho Protein ◽  
The Common ◽  
And Oxidative Stress

Calcineurin inhibitors (CNIs) are the most popular immunosuppressants in organ transplantation, but nephrotoxicity is a major concern. The common mechanism underlying chronic CNI nephropathy is oxidative stress, and the process of chronic CNI nephropathy is similar to that of aging. Current studies provide evidence that antiaging Klotho protein plays an important role in protecting against oxidative stress, and its signaling is a target for preventing oxidative stress-induced aging process. In this review, we focus on the association between Klotho and oxidative stress and the protective mechanism of action of Klotho against oxidative stress in chronic CNI nephropathy. In addition, we discuss the delivery strategy for Klotho in CNI-induced nephropathy.

scholarly journals P445 Efficacy and safety of induction therapy with calcineurin inhibitors followed by maintenance therapy with vedolizumab in severe ulcerative colitis: a large patient cohort with long-term follow-up

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S401-S401
Author(s):  
J OLLECH ◽  
S Dwadasi ◽  
I Normatov ◽  
A Israel ◽  
V Rai ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Maintenance Therapy ◽  
Median Time ◽  
Induction Therapy ◽  
Calcineurin Inhibitor ◽  
Calcineurin Inhibitors ◽  
Free Survival ◽  
Severe Ulcerative Colitis ◽  
Steroid Refractory

Abstract Background The options for the medical management of patients with severe ulcerative colitis failing IV steroids are limited and include the calcineurin inhibitors cyclosporin or tacrolimus, especially in patients who had previously failed anti-TNF agents. Following induction therapy with a calcineurin inhibitor, transitioning to vedolizumab as maintenance therapy could be an option. We report on the largest cohort of patients successfully induced with calcineurin inhibitors who were then transitioned to vedolizumab maintenance therapy. Methods We performed a retrospective observational study of adult ulcerative colitis patients followed at the University of Chicago Inflammatory Bowel Disease Center. Patients with severe steroid-refractory ulcerative colitis were included if they received a calcineurin inhibitor (ciclosporin or tacrolimus) as induction therapy followed by maintenance therapy with vedolizumab between January 2014 and December 2018. Patients who had a follow-up of fewer than three months were excluded. The primary endpoint was colectomy-free survival. Secondary endpoints included survival without vedolizumab discontinuation as well as clinical, steroid-free and biochemical remission at week 14. Results A total of 71 patients (59% male) were treated with vedolizumab after induction therapy with calcineurin inhibitors for severe steroid-refractory colitis. Truelove and Witts criteria for Acute Severe Ulcerative Colitis were fulfilled in 77% of patients, and 97% of patients had moderate to severe endoscopic disease. Patients were followed for a median time of 25 months (IQR 16–36). Colectomy free survival rates from vedolizumab initiation were 67% at one year and 55% at two years (Figure 1, Panel A). At the end of induction with vedolizumab at week 14, 50% of patients were in clinical remission, and 62% of patients had a normal CRP. At one and two years following vedolizumab initiation, 43% and 28% of patients were still on vedolizumab, respectively (Figure 1, Panel B). Vedolizumab was dose escalated to infusions every four weeks in 44% of patients. The median time to dose escalation was 5.6 months (IQR 4.1–8.2). No serious adverse events were recorded in our patient cohort. Conclusion Transitioning to vedolizumab following induction of remission with calcineurin inhibitors is effective and safe. Such a treatment strategy should be considered in patients with severe steroid-refractory ulcerative colitis, especially in cases of previous anti-TNF failure.

scholarly journals Calcineurin Inhibitor-Based Immunosuppression and COVID-19: Results from a Multidisciplinary Cohort of Patients in Northern Italy

2020 ◽  
Vol 8 (7) ◽  
pp. 977 ◽  
Author(s):  
Lorenzo Cavagna ◽  
Elena Seminari ◽  
Giovanni Zanframundo ◽  
Marilena Gregorini ◽  
Angela Di Matteo ◽  
...  
Keyword(s):  
Organ Transplantation ◽  
Calcineurin Inhibitor ◽  
Clinical Course ◽  
Solid Organ Transplantation ◽  
Calcineurin Inhibitors ◽  
Infectious Complications ◽  
Study Data ◽  
Solid Organ ◽  
The North

The role of immunosuppression in SARS-CoV-2-related disease (COVID-19) is a matter of debate. We here describe the course and the outcome of COVID-19 in a cohort of patients undergoing treatment with calcineurin inhibitors. In this monocentric cohort study, data were collected from the COVID-19 outbreak in Italy up to 28 April 2020. Patients were followed at our hospital for solid organ transplantation or systemic rheumatic disorders (RMDs) and were on calcineurin inhibitor (CNI)-based therapy. Selected patients were referred from the North of Italy. The aim of our study was to evaluate the clinical course of COVID-19 in this setting. We evaluated 385 consecutive patients (220 males, 57%; median age 61 years, IQR 48–69); 331 (86%) received solid organ transplantation and 54 (14%) had a RMD. CNIs were the only immunosuppressant administered in 47 patients (12%). We identified 14 (4%) COVID-19 patients, all transplanted, mainly presenting with fever (86%) and diarrhea (71%). Twelve patients were hospitalized and two of them died, both with severe comorbidities. No patients developed acute respiratory distress syndrome or infectious complications. The surviving 10 patients are now fully recovered. The clinical course of COVID-19 patients on CNIs is generally mild, and the risk of superinfection seems low.

scholarly journals A novel resistance pathway for calcineurin inhibitors in the human pathogenic Mucorales Mucor circinelloides

2019 ◽  
Author(s):  
Sandeep Vellanki ◽  
R. Blake Billmyre ◽  
Alejandra Lorenzen ◽  
Micaela Campbell ◽  
Broderick Turner ◽  
...  
Keyword(s):  
Amino Acid ◽  
Calcineurin Inhibitor ◽  
Calcineurin Inhibitors ◽  
Hyphal Growth ◽  
Mucor Circinelloides ◽  
Wild Type ◽  
Yeast Growth ◽  
Amino Acid Permease ◽  
In The Wild ◽  
Calcineurin Activity

AbstractMucormycosis is an emerging lethal fungal infection in immunocompromised patients. Mucor circinelloides is a causal agent of mucormycosis and serves as a model system to understand genetics in Mucorales. Calcineurin is a conserved virulence factor in many pathogenic fungi and calcineurin inhibition or deletion of the calcineurin regulatory subunit (CnbR) in Mucor results in a shift from hyphal to yeast growth. We analyzed thirty-six calcineurin inhibitor resistant or bypass mutants that exhibited hyphal growth in the presence of calcineurin inhibitors or in the yeast-locked cnbRΔ mutant background without carrying any mutations in known calcineurin components. We found that a majority of the mutants had altered sequence in a gene, named here bycA (bypass of calcineurin A). bycA encodes an amino acid permease. We verified that both bycAΔ, and the bycAΔ cnbRΔ double mutant are resistant to the calcineurin inhibitor FK506, thereby demonstrating a novel resistance mechanism against calcineurin inhibitors. We also found that the expression of bycA was significantly higher in the wild type strain treated with FK506 and in the cnbRΔ mutants, but significantly lower in the wild type without FK506. These findings suggest that bycA is a negative regulator of hyphal growth and/or a positive regulator of yeast growth in Mucor and calcineurin suppresses the bycA gene at the mRNA level to promote hyphal growth. BycA is involved in the Mucor hyphal-yeast transition as our data demonstrates a positive correlation between bycA expression, protein kinase A activity, and Mucor yeast-growth. Also calcineurin, independent of its role in morphogenesis, contributes to virulence traits including phagosome maturation blockade, host cell damages, and pro-angiogenic growth factor induction during interactions with hosts.ImportanceMucor is intrinsically resistant to most known antifungals, which makes mucormycosis treatment challenging. Calcineurin is a serine/threonine phosphatase widely conserved across eukaryotes. When calcineurin function is inhibited in Mucor, growth shifts to a less-virulent yeast growth form which makes calcineurin an attractive target for development of new antifungal drugs. Previously we identified two distinct mechanisms through which Mucor can become resistant to calcineurin inhibitors involving Mendelian mutations in the gene for FKBP12, calcineurin A or B subunits and epimutations silencing the FKBP12 gene. Here, we identified a third novel mechanism where loss of function mutations in the amino acid permease encoding the bycA gene contribute to resistance against calcineurin inhibitors. When calcineurin activity is absent, BycA can activate PKA to promote yeast growth via a cAMP-independent pathway. Our data also shows that calcineurin activity, primarily contributes to host - pathogen interactions in the pathogenesis of Mucor.

scholarly journals A Novel Resistance Pathway for Calcineurin Inhibitors in the Human-Pathogenic Mucorales Mucor circinelloides

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sandeep Vellanki ◽  
R. Blake Billmyre ◽  
Alejandra Lorenzen ◽  
Micaela Campbell ◽  
Broderick Turner ◽  
...  
Keyword(s):  
Calcineurin Inhibitor ◽  
Wild Type Strain ◽  
Calcineurin Inhibitors ◽  
Hyphal Growth ◽  
Mucor Circinelloides ◽  
Wild Type ◽  
Yeast Growth ◽  
Amino Acid Permease ◽  
In The Wild ◽  
Calcineurin Activity

ABSTRACT Mucormycosis is an emerging lethal fungal infection in immunocompromised patients. Mucor circinelloides is a causal agent of mucormycosis and serves as a model system to understand genetics in Mucorales. Calcineurin is a conserved virulence factor in many pathogenic fungi, and calcineurin inhibition or deletion of the calcineurin regulatory subunit (CnbR) in Mucor results in a shift from hyphal to yeast growth. We analyzed 36 calcineurin inhibitor-resistant or bypass mutants that exhibited hyphal growth in the presence of calcineurin inhibitors or in the yeast-locked cnbRΔ mutant background without carrying any mutations in known calcineurin components. We found that a majority of the mutants had altered sequence in a gene, named here bycA (bypass of calcineurin). bycA encodes an amino acid permease. We verified that both the bycAΔ single mutant and the bycAΔ cnbRΔ double mutant are resistant to calcineurin inhibitor FK506, thereby demonstrating a novel mechanism of resistance against calcineurin inhibitors. We also found that the level of expression of bycA was significantly higher in the wild-type strain treated with FK506 and in the cnbRΔ mutants but was significantly lower in the wild-type strain without FK506 treatment. These findings suggest that bycA is a negative regulator of hyphal growth and/or a positive regulator of yeast growth in Mucor and that calcineurin suppresses expression of the bycA gene at the mRNA level to promote hyphal growth. BycA is involved in the Mucor hypha-yeast transition as our data demonstrate positive correlations among bycA expression, protein kinase A activity, and Mucor yeast growth. Also, calcineurin, independently of its role in morphogenesis, contributes to virulence traits, including phagosome maturation blockade, host cell damages, and proangiogenic growth factor induction during interactions with hosts. IMPORTANCE Mucor is intrinsically resistant to most known antifungals, which makes mucormycosis treatment challenging. Calcineurin is a serine/threonine phosphatase that is widely conserved across eukaryotes. When calcineurin function is inhibited in Mucor, growth shifts to a less virulent yeast growth form, which makes calcineurin an attractive target for development of new antifungal drugs. Previously, we identified two distinct mechanisms through which Mucor can become resistant to calcineurin inhibitors involving Mendelian mutations in the gene for FKBP12, including mechanisms corresponding to calcineurin A or B subunits and epimutations silencing the FKBP12 gene. Here, we identified a third novel mechanism where loss-of-function mutations in the amino acid permease corresponding to the bycA gene contribute to resistance against calcineurin inhibitors. When calcineurin activity is absent, BycA can activate protein kinase A (PKA) to promote yeast growth via a cAMP-independent pathway. Our data also show that calcineurin activity contributes to host-pathogen interactions primarily in the pathogenesis of Mucor.

scholarly journals Podocytes

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 114 ◽  
Author(s):  
Jochen Reiser ◽  
Mehmet M. Altintas
Keyword(s):  
Glomerular Filtration ◽  
Structural Changes ◽  
Dynamic Network ◽  
Active Role ◽  
Renal Diseases ◽  
Glomerular Diseases ◽  
Current State ◽  
Kidney Glomerulus ◽  
Cytoskeletal Dynamics ◽  
Foot Process

Podocytes are highly specialized cells of the kidney glomerulus that wrap around capillaries and that neighbor cells of the Bowman’s capsule. When it comes to glomerular filtration, podocytes play an active role in preventing plasma proteins from entering the urinary ultrafiltrate by providing a barrier comprising filtration slits between foot processes, which in aggregate represent a dynamic network of cellular extensions. Foot processes interdigitate with foot processes from adjacent podocytes and form a network of narrow and rather uniform gaps. The fenestrated endothelial cells retain blood cells but permit passage of small solutes and an overlying basement membrane less permeable to macromolecules, in particular to albumin. The cytoskeletal dynamics and structural plasticity of podocytes as well as the signaling between each of these distinct layers are essential for an efficient glomerular filtration and thus for proper renal function. The genetic or acquired impairment of podocytes may lead to foot process effacement (podocyte fusion or retraction), a morphological hallmark of proteinuric renal diseases. Here, we briefly discuss aspects of a contemporary view of podocytes in glomerular filtration, the patterns of structural changes in podocytes associated with common glomerular diseases, and the current state of basic and clinical research.

Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results

2018 ◽  
Vol 36 (25) ◽  
pp. 2612-2620 ◽  
Author(s):  
Jacques Dantal ◽  
Emmanuel Morelon ◽  
Lionel Rostaing ◽  
Eric Goffin ◽  
Anabelle Brocard ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Kidney Transplant ◽  
Squamous Cell ◽  
Calcineurin Inhibitor ◽  
Calcineurin Inhibitors ◽  
Squamous Cell Carcinomas ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Skin Cancers

Purpose Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow-up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor–based immunosuppression. Methods Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group ( P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas ( P < .001), 34% versus 66% for other skin cancers ( P < .001), and 20% versus 37.5% for basal cell carcinomas ( P < .05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory.

Post-Renal Transplant De Novo Non-Skin Malignancies in Mycophenolate Mofetil- and Calcineurin Inhibitor-Based Immunosuppression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1683-1683
Author(s):  
Lohith Bachegowda ◽  
Diptesh Gupta ◽  
Ajoy Bharadwaj ◽  
Karthik Ranganna ◽  
TIM Adamowicz ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Renal Transplant ◽  
Calcineurin Inhibitor ◽  
De Novo ◽  
Calcineurin Inhibitors ◽  
Solid Organ ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Hla Antigen ◽  
Post Transplant

Abstract Abstract 1683 Poster Board I-709 Introduction- Post-transplant malignancy is one of the major complications of immunosuppression in kidney transplant recipients. Mycophenolate Mofetil(MMF) and Calcineurin inhibitors(CNI) based immunosuppression is a well established combination in clinical practice. MMF has an action on cell proliferation by inhibiting Inosine Mono Phosphate dehydrogenase. However, its antitumor properties have been constantly debated. It is shown to have some antiproliferative effects in leukemias and lymphomas with a decreased incidence of PTLD. This single center study evaluated the effect of combining mycophenolate mofetil (MMF) with calcineurin inhibitors on the incidence of de novo post-transplant non skin malignancies in renal transplant recipients. We also compared the incidence of solid versus liquid cancers. Patients and Methods- Six hundred and fifty seven (657) consecutive kidney and kidney/pancreas recipients transplanted between January 2000 and December 2005 were analyzed for post-transplant malignancies. Three hundred and sixty two (362) recipients were maintained on a calcineurin inhibitor and MMF combination. The incidence of neoplasm in this group was monitored till June 2009. All patients received induction therapy with basiliximab and methylprednisolone. Steroid therapy was discontinued after the second dose in the withdrawal group. In the steroid treated group oral prednisone was initiated on day 2 at 30 mg per day and rapidly tapered to 5 mg per day at one month and continued for the life of the graft. Maintenance therapy in all recipients included both, a calcineurin inhibitor and mycophenolate mofetil (MMF). All clinical acute rejections were confirmed by biopsy and treated with intravenous methylprednisolone. Steroid unresponsive rejections were treated with Thymoglobulin Table 1 shows the demography in the CNI + MMF recipient group Recipient demography Calcineurin inhibitor/MMF group Number of recipients 362 Mean age in years 53 ± 3 Male gender 196 Deceased donor kidney recipients 305 Mean HLA antigen mismatch 3.95 ± 2.6 Pre-transplant malignancies 0 Number of recipients with rejection 71 Table 2 Incidence and type of malignancies in calcineurin inhibitor + MMF group Type of cancer Calcineurin inhibitor/MMF group Total number of recipients 362 Post transplant lymphoproliferative disease 1 Hodgkin's lymphoma 1 Renal cell cancer 6 Lung cancer 3 Prostate cancer 2 Colon cancer 2 Breast cancer 2 Bladder cancer 1 Pancreatic cancer 1 Leukemia 1 Thyroid cancer 1 Total cancers 21 (5.8%) Conclusion In our study on CNI/MMF based immunosuppression in renal transplant patients, 5.8% developed various neoplasms. There was a lower incidence of hematologic- malignancies 3/362(0.8%) in comparison to solid organ neoplasm 18/362(4.97%). The incidence of PTLD was 0.27%, which is similar to other observational studies. This could partly be due to greater expression of Inosine Monophosphate, inhibited by MMF in malignant hematologic cells. Further multicenter analysis needs to be done to detect the incidence of liquid and solid neoplasms, correlating with intracellular IMP levels with MMF usage in renal transplant recipients. Disclosures No relevant conflicts of interest to declare.

scholarly journals The cell biology of renal filtration

2015 ◽  
Vol 209 (2) ◽  
pp. 199-210 ◽  
Author(s):  
Rizaldy P. Scott ◽  
Susan E. Quaggin
Keyword(s):  
Cell Biology ◽  
Molecular Size ◽  
Renal Glomerulus ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Glomerular Function ◽  
Selective Filter ◽  
Circulating Cells ◽  
Filtration Barrier ◽  
Glomerular Capillaries

The function of the kidney, filtering blood and concentrating metabolic waste into urine, takes place in an intricate and functionally elegant structure called the renal glomerulus. Normal glomerular function retains circulating cells and valuable macromolecular components of plasma in blood, resulting in urine with just trace amounts of proteins. Endothelial cells of glomerular capillaries, the podocytes wrapped around them, and the fused extracellular matrix these cells form altogether comprise the glomerular filtration barrier, a dynamic and highly selective filter that sieves on the basis of molecular size and electrical charge. Current understanding of the structural organization and the cellular and molecular basis of renal filtration draws from studies of human glomerular diseases and animal models of glomerular dysfunction.

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