Targeting Inflammation and Podocytopathy in Chronic Kidney Disease

Targeting Inflammation and Podocytopathy in Chronic Kidney Disease

Thursday, September 8, 2016

The New York Academy of Sciences

Incidence of chronic kidney disease (CKD) is increasing, most notably in older populations and with co-morbidities such as diabetes or hypertension. Accumulating evidence supports a role for renal inflammation and podocytopathy in the pathogenesis and progression of CKD, but to date no anti-inflammatory therapy has been tested in a phase III trial in patients with stage III-IV CKD. While disruption of podocyte integrity appears to be important in disease progression, it is unknown whether restoring podocyte function or preventing further podocyte loss can improve filtration barrier integrity and halt progression of CKD.

This symposium will focus on new insights into renal inflammatory pathobiology and the mechanisms of podocyte dysfunction to help guide innovative therapeutic approaches for this growing health concern. The symposium will also address areas of knowledge gaps, including the nature of the infiltrating immune cell type, the temporal contribution of inflammation to human disease progression, and the safety of anti-inflammatory drugs in patient populations prone to infections (including persons with diabetes).

*Reception to follow.

Registration Pricing

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Member (Student / Postdoc / Resident / Fellow)$25
Nonmember (Academia)$105
Nonmember (Corporate)$160
Nonmember (Non-profit)$105
Nonmember (Student / Postdoc / Resident / Fellow)$70

Webinar Pricing

This event will also be broadcast as a webinar; registration is required.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City where possible.

Member$30
Member (Student / Postdoc / Resident / Fellow)$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45

Agenda

* Presentation times are subject to change.


Thursday, September 8, 2016

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Carine Boustany, PhD, PharmD, Boehringer Ingelheim Pharmaceutical

Plenary Session I: Inflammation

9:15 AM

Leveraging CKD Human Genetics in Drug Discovery
Myung K. Shin, PhD, Merck & Co. Inc

9:50 AM

Chronic Inflammation as a Key Driver in CKD: From Systems Biology to Clinical Trials
Matthias Kretzler, MD, University of Michigan

10:25 AM

Networking Coffee Break

10:55 AM

Cathepsin S as a Mediator and Therapeutic Target in Diabetes-related CKD
Hans-Joachim Anders, MD, University of Munich

11:30 AM

Soluble Urokinase Receptor and Mechanism of Chronic Kidney Disease
Jochen Reiser, MD, PhD, Rush University Medical Center

Data Blitz Presentations

12:05 PM

Blockade of the Chemokine Receptor CX3CR1 with a Single Chain Antibody Reduces the Progression of Atherosclerosis and Glomerulosclerosis in Mice
Steven Kerr, MS, CardioMetabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals

12:15 PM

Mathematical Modeling of Glucose Sensitivity of Intracellular Renin-Angiotensin System in Podocytes
Ashlee N. Ford Versypt, PhD, Oklahoma State University

12:25 PM

Networking Lunch and Poster Session

Plenary Session II: Podocytopathy

1:55 PM

Podocytes: The Weakest Link in Diabetic Kidney Disease?
Katalin Susztak, MD, PhD, University of Pennsylvania
* Presenter slides will not be included as part of the Webinar broadcast

2:30 PM

Role of Glomerular Cell Crosstalk in Kidney Disease
John Cijiang He, MD, PhD, Icahn School of Medicine at Mount Sinai

3:05 PM

Networking Coffee Break

3:35 PM

Podometrics as a Tool for Glomerular Disease Investigation and Monitoring
Roger C. Wiggins, MB, BChir, University of Michigan

4:10 PM

Mechanical Challenges to the Glomerulus: Restoring Filtration Barrier Integrity
Kevin V. Lemley, MD, PhD, University of Southern California

4:45 PM

Poster Prize Awards and Closing Remarks
Scott MacDonnell, PhD, Regeneron Pharmaceuticals

5:00 PM

Networking Reception

6:00 PM

Adjourn

Organizers

Carine Boustany, PhD, PharmD

Boehringer Ingelheim Pharmaceutical

Dr. Carine Boustany is a Director of External Innovation in Cardiometabolic Diseases Research at Boehringer Ingelheim. In this role, Carine is responsible for leading a team aimed at identifying new drug targets for the treatment of Chronic Kidney Disease. Prior to joining BI in 2011, Carine was a Research Project Leader at Pfizer where she was responsible for diabetes and diabetic nephropathy programs. Carine was also an Assistant Professor at the Lebanese International University (Beirut, Lebanon) and at the Holy Spirit University (Kaslik, Lebanon). Consistent with her experience spanning preclinical to clinical research, Carine's education includes a PharmD degree from Saint-Joseph University (Beirut, Lebanon), followed by a PhD in Pharmaceutical Sciences from the College of Pharmacy at the University of Kentucky (Lexington, Kentucky), and a post-doctoral fellowship at the University of Kentucky focused on investigating the role of components of the renin-angiotensin system in the metabolic syndrome.

Scott MacDonnell, PhD

Regeneron Pharmaceuticals

Dr. Scott MacDonnell obtained his undergraduate and master's degrees in exercise physiology from the University of Delaware and completed his doctoral work in cardiovascular physiology at Temple University in Philadelphia, PA. He completed a post-doctoral fellowship at Temple University Medical School in the lab of Dr. Steve Houser. His fellowship research focused on identifying mechanisms responsible for the pathogenesis of heart failure. Specifically, his work examined the role of CaMKII in altered contractility, myocytes apoptosis, and transcriptional regulation associated with heart failure progression. This work has been published in Circulation Research and recognized as a best manuscript by the editorial board in 2010. Additionally, Scott was recognized by the International Society for Heart Research and awarded the young investigator of the year in 2008. Scott worked for 8-years as a principal scientist at Boehringer Ingelheim within the department of CardioMetabolic Disease Research where his research focused on identifying novel therapeutic treatment options for chronic kidney disease, heart failure, and fibrosis. Scott currently works at Regeneron Pharmaceuticals in the department of Cardiovascular and Renal Disease where he leads an in-vitro group supporting both screening and functional assay development for heart failure, hypertension, pulmonary fibrosis and hypertension, and both acute and chronic renal indications.

Jay J. Kuo, PhD

Boehringer Ingelheim Pharmaceutical

Jay Kuo is a scientist in the Cardiometabolic Disease Department at Boehringer Ingelheim Pharmaceuticals. He received his PhD in Pharmacology from the University of Minnesota followed by post-doctoral research at the University of Mississippi Medical Center studying the cardiovascular, metabolic, and renal effects of the hypothalamic melanocortin system. Following his post-doctoral studies, he developed pre-clinical in vivo models to support small molecule therapeutic programs at Nitromed and at Surface Logix. He joined Boehringer Ingelheim in 2010 and is currently a laboratory head in the External Innovation group that is focused on the discovery and advancement of novel therapeutic concepts for the treatment of diabetic nephropathy.

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy of Sciences

Speakers

Hans-Joachim Anders, MD

University of Munich

H.J. Anders received his training in nephrology and rheumatology at the University of Munich in Germany and now directs the Department of Nephrology at the inner city campus. He runs a lupus nephritis clinic and also his experimental research is focussed on the molecular and cellular mechanisms of glomerulonephritis and kidney remodelling. His group makes efforts to accelerate translational research in immune-mediated kidney disease for a better understanding of disease pathophysiology and better treatment options.

John Cijiang He, MD, PhD

Icahn School of Medicine at Mount Sinai

Dr. John Cijiang He got his MD at Shanghai Second medical University and PhD in Physiology at University of Paris VII, France. He was a visiting scientist at NIH in Maryland and The Picower Institute for Medical Research in New York. He completed his medical residency at SUNY down state and clinical nephrology fellowship at Mount Sinai Hospital in New York. Currently, he is a tenured full Professor of Medicine and Pharmacology/Systems Therapeutics at Icahn School of Medicine at Mount Sinai. He holds the title of Irene and Dr. Arthur Fishberg endowed chair of Nephrology. He is the division chief of Nephrology at Mount Sinai Health System. He is currently the president of Chinese American Society of Nephrology. His major research areas include podocyte biology and pathology, signaling networks in kidney cells, systems biology of kidney disease, and kidney fibrosis. His major clinical interest includes diabetic kidney disease, viral-induced kidney disease, and primary glomerular disease. He is the member for NIH and VA study section. He has been well-funded by NIH and VA. He has published more than 150 peer-reviewed papers in the high impact journals.

Steven Kerr, MS

Boehringer Ingelheim Pharmaceuticals

Steven Kerr is a Sr. Scientist in the Cardiometabolic Disease Department at Boehringer Ingelheim Pharmaceuticals. He received his BS degree in biology from the University of Michigan and his MS degree in biochemistry from Wayne State University. His research background includes developing therapies for cardiovascular diseases such hypertension, heart failure, and atherosclerosis, as well as the role of inflammation in the pathology of chronic kidney disease. Steven is a lab head centering his research on the development of new in vivo models of chronic kidney disease with an emphasis on cardiovascular involvement. His group is responsible for the development and testing of new therapeutic agents for the treatment of diseases associated with nephropathy and cardiovascular injury.

Matthias Kretzler, MD

University of Michigan

Matthias Kretzler, MD is a Professor of Internal Medicine/Nephrology and Computational Medicine and Bioinformatics. He is PI of the Multidisciplinary research team in diabetic endorgan damage at U Michigan, the U54 Nephrotic Syndrome Research Network (NEPTUNE) in the Rare Disease Clinical Research Network II, Director of the Applied Systems Biology Core in the O'Brien Renal Center at UMichigan. He has 18 years of experience in integration of bioinformatics, molecular and clinical approaches in more than 200 collaborative studies. He and his team focus is on interdisciplinary data integration of large-scale data sets generated in prospective cohort studies of CKD across species, tissues and diseases. Using systems biology approaches he and his team defines regulatory networks activated in human glomerular diseases. This approach has allowed the identification and validation of molecular prognostic biomarkers of chronic kidney disease and successful developments of molecularly targeted therapies in glomerular disease in public-private partnerships.

Kevin V. Lemley, MD, PhD

University of Southern California

Dr. Lemley is Professor of Pediatrics at the University of Southern California Keck School of Medicine and Attending Nephrologist at Children's Hospital Los Angeles. His MD and PhD (Physiology) degrees are from Stanford University, where he was also on the faculty for 8 years. He has been funded by the National Institutes of Health, the American Diabetes Assocation and other national funding agencies. He was a Fellow of the Alexander von Humboldt Foundation (Germany). He is a member of the American Pediatric Society. He is an advisor to the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH. He has a thirty-year history of research on the biology and pathobiology of the podocyte and in structural studies on the kidney in humans and experimental animals. His main research interests are podocyte cell biology and pathobiology, stems cells in therapy of kidney disease, morphometric studies of kidney disease and mathematical modeling. His main clinical interests are diabetic kidney disease, glomerular disease, nephrotic syndrome and genetic diseases of the kidneys.

Jochen Reiser, MD, PhD

Rush University Medical Center

Jochen Reiser, MD, PhD is the chairman of the Department of Medicine at Rush University Medical Center and the Ralph C. Brown, MD professor of Medicine at Rush University. Dr. Reiser is a world-renowned research leader in the field of kidney disease with a heavy focus on molecular biology and genetics. He has published more than 145 papers, many of them in highest impact journals. His contributions range from identification of the first circulating factor known to start the process leading to focal segmental glomerulosclerosis as well as to general mechanisms of chronic kidney disease. His work started new research fields and significantly advanced new treatment options for this disease. Dr. Reiser directs a NIH-funded research laboratory in renal disease and biomedical investigation. He is a member of the American Society for Clinical Investigation (ASCI), the American Clinical and Climatological Society (ACCA) and the Association of American Physicians (AAP). Dr. Reiser earned his medical degree and PhD (summa cum laude) at the Ruprecht Karls University of Heidelberg, Germany and served his residency in internal medicine at the Albert Einstein College of Medicine in New York. He completed his fellowship in nephrology at Massachusetts General Hospital and Brigham and Women's Hospital at Harvard Medical School in Boston. He then was an assistant professor at Harvard Medical School and the founding director of the program in glomerular disease at the Massachusetts General Hospital. Prior to arriving at Rush in September of 2012, Dr. Reiser was a professor of medicine, anatomy and cell biology, vice chairman for research in the department of medicine, and chief of the division of nephrology and hypertension at University of Miami Leonard M. Miller School of Medicine. There, he also served as the Interim Chairman of Medicine. With his appointment to Rush, Dr. Reiser became the youngest chairperson of internal medicine at an academic medical center in the United States. Since his tenure at Rush, the department has grown by more than 100 members to a size of 500 faculty and his improvements largely impacted on the financial and academic growth of the entire Rush system.

Myung Shin, PhD

Merck & Co. Inc.

Myung Shin received his BA from Northwestern University and PhD from University of California-Berkeley. He was a Jane Coffin Childs Postdoc Fellow at Princeton University and Associate Member at Fox Chase Cancer Center prior to joining Merck. For about a decade, he led efforts to identify novel technologies for making Genetically Engineered Models for all therapeutic and functional areas across Merck. More recently, he became the Genetics Lead within the GpGx Department to identify and validate novel human genetics targets within the cardio-metabolic diseases area.

Katalin Susztak, MD, PhD

University of Pennsylvania

Dr. Katalin Susztak is a physician-scientist at the University of Pennsylvania. Her laboratory is interested in understanding the pathomechanism of chronic kidney disease development. Her laboratory uses next generation sequencing methods and a large collection of human kidney tissue samples to identify novel pathways and biomarkers. At present there are more than 1,400 kidney tissue samples in her Biobank. The samples are carefully annotated with functional (eGFR, albuminuria) and structural (glomerulosclerosis and tubulointerstitial fibrosis) parameters. RNAsequencing analysis has been completed for more than 600 microdissected glomerular and tubular samples. These discovery approaches are complemented with careful cell and molecular biological studies to define the role of individual genes and pathways. This analysis identified a concerted dysregulation of immune system, metabolic and developmental genes (Niranjan et al. Nature Medicine 2008, Kang et al Nature Medicine 2015). While transcript level differences can highlight important changes in human CKD, we believe that integrating these results with genetic and epigenomic studies will be essential to identify causal pathways for CKD development. As such her laboratory has been part of the NIH Roadmap Epigenomics Projects to characterize the epigenome of healthy and diseased kidneys. Dr. Susztak has been the recipient of the 2011 Young Investigator Award of the American Society of Nephrology and American Heart Association; one of the most prestigious award given to researchers under the age of 41 in the field of nephrology. Her laboratory is supported by the National Institute of Health, the American Diabetes Association, the Juvenile Diabetes Research Foundation and private sources.

Ashlee N. Ford Versypt, PhD

Oklahoma State University

Professor Ashlee N. Ford Versypt holds three degrees in chemical engineering: a BS from the University of Oklahoma and an MS and a PhD from the University of Illinois at Urbana–Champaign. As an undergraduate student, Professor Ford Versypt was named the Outstanding Chemical Engineer Senior in the University of Oklahoma College of Engineering and graduated summa cum laude. During graduate school, Professor Ford Versypt was awarded the Department of Energy Computational Science Graduate Fellowship and the National Science Foundation Graduate Research Fellowship. Professor Ford Versypt spent a summer as a graduate research intern in the Computational Science Center at Brookhaven National Laboratory. In 2013, Professor Ford Versypt was recognized as the Frederick A. Howes Scholar in Computational Science, which is awarded annually to a recent alumnus of the DOE Computational Science Graduate Fellowship for outstanding leadership, character, and technical achievement. In 2012–2014, Professor Ford Versypt was a postdoctoral research associate with Professor Richard Braatz in the Department of Chemical Engineering at the Massachusetts Institute of Technology. Currently, Professor Ford Versypt is an assistant professor in the School of Chemical Engineering at Oklahoma State University. She also holds an appointment in the Harold Hamm Diabetes Center at the University of Oklahoma Health Sciences Center.

Roger C. Wiggins, MB, BChir

University of Michigan

Roger C. Wiggins was raised in Zimbabwe in Africa, received undergraduate and graduate training at Cambridge University in England and London Teaching Hospitals, and research training at Scripps Clinic and Research Foundation in La Jolla, California. He was recruited to the University of Michigan, Ann Arbor in 1981 where he served as Director of the Nephrology Training Program for 10 years, Division Chief of Nephrology for 15 years, and Director of the NIH-supported O'Brien Kidney Center for 23 years. His long-standing research focus has been podocyte biology and defining the role of podocyte depletion in progression of glomerular diseases ("The podocyte depletion hypothesis"). A recent focus has been on how podocyte parameters can be harnessed to monitor and manage prevention of glomerular disease progression in the clinic ("podometrics"). He has received various awards including the John P. Peters Award from the American Society of Nephrology in 2015.

Sponsors

Grant Support

This program is supported by an educational grant from AstraZeneca.

Promotional Partners

Advances in Chronic Kidney Disease

The American Association of Kidney Patients

American Journal of Kidney Diseases

American Society of Nephrology (ASN)

American Transplant Foundation

Kidney International

National Kidney Foundation

Nature

Nephcure

Seminars in Nephrology


The Biochemical Pharmacology Discussion Group is proudly supported by:

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Premiere Supporter

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Abstracts

Leveraging CKD Human Genetics in Drug Discovery
Myung K. Shin, PhD, Merck & Co. Inc.

Recent discoveries findings in human genetics holds promise of identifying novel therapeutic targets for CKD. In this talk, we will cover the current landscape of leveraging Human Genetics in Drug Discovery and the challenges on identifying and validating causal gene from GWAS findings.

Chronic Inflammation as a Key Driver in CKD: From Systems Biology to Clinical Trials
Matthias Kretzler, MD, University of Michigan

Chronic Kidney diseases are currently grouped using descriptive disease classification lumping multiple disease with different mechanism together. The lack of a mechanistic basis in the current glomerular disease taxonomy has significant consequences for both routine clinical care and identification of novel disease mechanism as starting points for therapeutic targets and biomarkers. Even if a biomarker or therapy is effectively targets a disease mechanism, the impact of the treatment is diluted out among the patients with a different mechanism not targeted by the intervention. This provides the rational for molecular based disease definition, enabling targeted therapy towards the disease mechanism destroying nephrons in a set of individuals. A critical element to make progress towards a precision medicine approach is the definition of the disease in a holistic manner using prospective cohort studies. The key element of this strategy is to develop and implement a protocol, which captures all elements of the disease manifestation during initiation and progression. This approach has become feasible with the current advances in molecular and clinical medicine. Implementation of this strategy to obtain comprehensive genetic, molecular, structural, clinical, environmental and socio-economic aspects of diseases in multicenter research settings will be presented. Examples how integrating these multi-scalar data sets allowed to define chronic inflammatory mechanism's cutting across these knowledge domains to driven the disease progression will be given. Subsequent identification of non-invasive biomarkers and development of anti-inflammatory compounds in glomerular diseases documented the feasibility of this approach to develop therapeutic strategies for CKD.

Cathepsin S as a Mediator and Therapeutic Target in Diabetes-related CKD
Hans-Joachim Anders, MD, University of Munich

Endothelial dysfunction is a central pathomechanism in diabetes complications. We speculated on a pathogenic role of cathepsin S (Cat-S), a cysteine protease known to degrade elastic fibers and to activate protease-activated receptor (PAR)-2. We found recombinant Cat-S to induce albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role of intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impairs the integrity and barrier function of glomerular endothelial cells selectively via PAR2. In human and mouse type 2 diabetic nephropathy only CD68+ intrarenal monocytes expressed Cat-S mRNA, while Cat-S protein was present also along endothelial cells and inside proximal tubular epithelial cells. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Late onset Cat-S or PAR2 inhibition consistently attenuated albuminuria and glomerulosclerosis as indicators of diabetic nephropathy in type 2 diabetic db/db mice. Late onset Cat-S or PAR2 inhibition also attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy in the same mice. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease, e.g. in diabetes.

Soluble Urokinase Receptor and Mechanism of Chronic Kidney Disease
Jochen Reiser, MD, PhD, Rush University Medical Center

Soluble urokinase receptor (suPAR) is typically a three domain signaling protein that can be released into the circulation by the cleavage of membrane bound uPAR. It is considered a broad marker of immune activation and was found to be a direct pathogen in podocytopathies like Focal and Segmental Glomerulosclerosis (FSGS). In FSGS, elevated plasma suPAR binds to and activates αvβ3 integrin on podocytes causing their structural rearrangement and proteinuria. suPAR can cooperate with CD40 auto-antibodie and is implicated in FSGS recurrence. More recent data unravels that suPAR is predictive of incident chronic kidney disease (CKD) and associates with future decline in already existing mild to moderate CKD. suPAR is also associated with future cardiovascular events in CKD patients further supporting a central role for this molecule in the pathogenesis of kidney disease and its complications. Novel studies pinpoint the source of suPAR excess to myeloid cells in the bone marrow and decipher important new interactions with genetic kidney disease risk factors such as APOL1.

Blockade of the Chemokine Receptor CX3CR1 with a Single Chain Antibody Reduces the Progression of Atherosclerosis and Glomerulosclerosis in Mice
Steven Kerr, MS, Boehringer Ingelheim Pharmaceuticals

The fractalkine receptor CX3CR1 regulates leukocyte trafficking during inflammation and is associated with cardiovascular disease risk. We developed a high-affinity, selective, single chain antibody that targets human CX3CR1, designated BI655088. Since cardiovascular disease is the major cause of morbidity and mortality in patients with chronic kidney disease, we used a cardiorenal model to evaluate atherosclerosis and renal parameters. Therefore, BI655088 was administered at 30mg/kg i.p. 2×/wk for 12 weeks to hyperlipidemic ApoE−/− mice expressing the human CX3CR1 gene and induced renal insufficiency by performing a ¾ nephrectomy. BI655088 significantly reduced atherosclerotic plaque area by 28% compared to vehicle-treated mice with no change in total cholesterol or triglycerides. In addition, BI655088 significantly reduced glomerulosclerosis incidence by 43% and severity in the remnant kidney. This effect was accompanied by a significant decrease in macrophage infiltration consistent with the mechanism of action. Plasma levels of fractalkine, used as a biomarker for antibody blockade of CX3CR1, were significantly increased in treated animals. In order to evaluate the potential effect of BI655088 for treating diabetic nephropathy, BI655088 was tested in streptozotocin-treated C57BL/6 mice transgenic for the human CX3CR1 gene. BI655088 dosed at 30, 3, and 0.3mg/kg i.p. 2×/wk for 12 weeks showed dose dependent decreases in both glomerulosclerosis, (−46%, −27%, and −15%), and interstitial lesions (−56%, −33%, and −16%), respectively, compared to vehicle-treated mice with no effect on glucose levels. These results demonstrate that treatment with the CX3CR1 antagonist BI655088 can mitigate both renal and vascular injury induced in diabetic and hyperlipidemic mouse models.

Mathematical Modeling of Glucose Sensitivity of Intracellular Renin-Angiotensin System in Podocytes
Ashlee N. Ford Versypt, PhD, Oklahoma State University

Podocytes express an intracellular renin-angiotensin system (RAS) that is altered in hyperglycemia. Studies have shown that the RAS peptide angiotensin II (ANG II) is modulated in hyperglycemic conditions and triggers podocyte injury and apoptosis. The progression of diabetic kidney disease could be slowed by controlling the ANG II levels to prevent irreversible podocyte loss. However, experimental evidence for glucose-dose-dependency of ANG II is scarce in the literature. Hence, for better understanding of the underlying mechanism, we use mathematical modeling to describe the glucose-stimulated RAS signaling in podocytes that produces ANG II. We have formulated a mathematical model to describe the glucose-sensitive reaction network that triggers the synthesis of ANG II. The local podocyte RAS signaling pathway is represented by a system of ordinary differential equations to track RAS peptides, enzymes, and receptors without explicit glucose-dependence. Literature experimental studies were used to estimate the unknown parameters and kinetic constants for the model under different glucose levels. The results showed a rise in ANG II levels with increasing glucose concentrations consistent with experimental observations. We were able to discriminate between possible models for the glucose dose-dependency of intracellular ANG II production in podocytes. The resulting model can be used to study the effect of different combinations of various ANG II modulating therapies such as ACE inhibitors, which could be useful for drug development.

Role of Glomerular Cell Crosstalk in Kidney Disease
John Cijiang He, MD, PhD, Icahn School of Medicine at Mount Sinai

Several lines of evidence suggest that glomerular cell crosstalk plays a major role in maintaining normal homeostasis of glomerular filtration unit. The alteration of glomerular cell crosstalk plays a major role in the progression of chronic kidney disease (CKD) such as diabetic nephropathy. For example, deficiency of VEGF-A from podocyte loss causes glomerular endothelial cell injury. Podocyte-specific overexpression of an active TBF-beta receptor induces glomerular endothelial cell oxidative stress probably through production of endothelin. The studies also suggest that eNOS is a key molecule mediating glomerular endothelial cell to podocytes crosstalk. Recently, we reported that knockdown of KLF2 specifically in endothelial cells induces more podocyte injury in diabetic mice. Using a podocyte depletion model, we confirmed that loss of podocytes can cause GEC injury through podocytes to GEC crosstalk. In addition, we have developed a double-labelled mouse model which allows us to sort both podocytes and glomerular endothelial cells (GEC) from the same mice. Using this approach we could perform RNA sequencing in both podocytes and GEC sorted from diabetic mice as compared to those of normal mice. We confirmed that VEGF signaling is a major pathway mediating podocytes to GEC crosstalk. Also, we identified several new mediators of crosstalk between podocytes and GEC. In conclusion, identification of the mechanism of crosstalk between glomerular cells will help us to develop new biomarkers and therapies for CKD.

Podometrics as a Tool for Glomerular Disease Investigation and Monitoring
Roger C. Wiggins, MB, BChir, University of Michigan

Podocytes are long-lived neuron-like epithelial cells of the glomerulus that carry cell-specific markers and have limited capacity for replacement. They must completely cover the filtration surface with foot processes to maintain the filtration barrier. Depletion of podocytes from glomeruli above a threshold value (about 30%) results in a protein leak into the filtrate and progressive glomerulosclerosis in proportion to the degree of depletion. Quantitation of degree of podocyte depletion in glomeruli and rate of podocyte detachment from glomeruli (measured non-invasively in urine) by "podometric" methodologies potentially provides a convenient approach towards monitoring the progression process and determining whether or not therapeutic interventions are effective. Podocyte density (number per glomerular tuft volume) decreases during normal aging as a result of a combination of decreased podocyte number per glomerulus and increasing glomerular volume. All progressive glomerular diseases are associated with accelerated podocyte detachment from glomeruli. During aging itself, and accelerated in all progressive glomerular diseases, as podocyte density decreases to approach a value of 100 per 106 um3 podocyte size must increase exponentially to compensate thereby causing hypertrophic stress and accelerated podocyte detachment that destabilizes the glomerulus such that it autonomously continues to lose podocytes eventually resulting in glomerulosclerosis. Podometric tools have potential to be clinically useful for monitoring and managing glomerular disease progression.

Mechanical Challenges to the Glomerulus: Restoring Filtration Barrier Integrity
Kevin V. Lemley, MD, PhD, University of Southern California

Podocyte loss is the common pathomechanism of chronic kidney disease progression in most forms of glomerular disease. Although initial mechanisms of podocyte loss differ, all forms seem to converge to a self-sustaining pathway of podocyte insufficiency itself leading to ongoing podocyte loss. Evidence has accumulated that many or most podocytes are shed from the glomerular capillary tuft as viable cells under these circumstances. We have recently suggested a specific mechanism of podocyte detachment as the result of the effects of elevated shear stress on podocyte foot processes due to enhanced flow through the filtration slits (as a part of adaptive hyperfiltration). This model in fact explains why angiotensin blockade is so effective at slowing the loss of function in progressive proteinuric renal diseases. It also suggests quite specific cellular targets to support sustained resistance to ongoing podocyte loss. Glomerular hypertrophy is an invariable consequence of the kidney's adaptive response to losses of functional mass. If this occurs without an adequate podocyte density, shear forces acting at the filtration slits will increase, increasing the mechanical challenge on the remaining podocytes and leading to their accelerated detachment. If podocyte density can be maintained despite glomerular hypertrophy and, most specifically, if total glomerular filtration slit length can be increased, then adaptive glomerular hyperfiltration can occur without excessive increases in shear forces in the filtration slits. This is reflected in an increase of the ultrafiltration coefficient and regression of proteinuria, which therefore represent reasonable target intermediate phenotypes for protective pharmacotherapy.

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