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Article ; Online: Role of biophysics and mechanobiology in podocyte physiology.

Haydak, Jonathan / Azeloglu, Evren U

2024 Volume 20, Issue 6, Page(s) 371–385

Abstract: Podocytes form the backbone of the glomerular filtration barrier and are exposed to various mechanical forces throughout the lifetime of an individual. The highly dynamic biomechanical environment of the glomerular capillaries greatly influences the cell ...

Abstract	Podocytes form the backbone of the glomerular filtration barrier and are exposed to various mechanical forces throughout the lifetime of an individual. The highly dynamic biomechanical environment of the glomerular capillaries greatly influences the cell biology of podocytes and their pathophysiology. Throughout the past two decades, a holistic picture of podocyte cell biology has emerged, highlighting mechanobiological signalling pathways, cytoskeletal dynamics and cellular adhesion as key determinants of biomechanical resilience in podocytes. This biomechanical resilience is essential for the physiological function of podocytes, including the formation and maintenance of the glomerular filtration barrier. Podocytes integrate diverse biomechanical stimuli from their environment and adapt their biophysical properties accordingly. However, perturbations in biomechanical cues or the underlying podocyte mechanobiology can lead to glomerular dysfunction with severe clinical consequences, including proteinuria and glomerulosclerosis. As our mechanistic understanding of podocyte mechanobiology and its role in the pathogenesis of glomerular disease increases, new targets for podocyte-specific therapeutics will emerge. Treating glomerular diseases by targeting podocyte mechanobiology might improve therapeutic precision and efficacy, with potential to reduce the burden of chronic kidney disease on individuals and health-care systems alike.
MeSH term(s)	Podocytes/physiology ; Humans ; Biomechanical Phenomena ; Mechanotransduction, Cellular/physiology ; Cytoskeleton/physiology ; Biophysics ; Animals ; Cell Adhesion/physiology
Language	English
Publishing date	2024-03-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2490366-8
ISSN	1759-507X ; 1759-5061
ISSN (online)	1759-507X
ISSN	1759-5061
DOI	10.1038/s41581-024-00815-3
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Article ; Online: cGAS Activation Accelerates the Progression of Autosomal Dominant Polycystic Kidney Disease.

Yoo, Miran / Haydak, Jonathan C / Azeloglu, Evren U / Lee, Kyung / Gusella, G Luca

Journal of the American Society of Nephrology : JASN

2024 Volume 35, Issue 4, Page(s) 466–482

Abstract: Significance statement: The renal immune infiltrate observed in autosomal polycystic kidney disease contributes to the evolution of the disease. Elucidating the cellular mechanisms underlying the inflammatory response could help devise new therapeutic ... ...

Abstract	Significance statement: The renal immune infiltrate observed in autosomal polycystic kidney disease contributes to the evolution of the disease. Elucidating the cellular mechanisms underlying the inflammatory response could help devise new therapeutic strategies. Here, we provide evidence for a mechanistic link between the deficiency polycystin-1 and mitochondrial homeostasis and the activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of the interferon genes (STING) pathway. Our data identify cGAS as an important mediator of renal cystogenesis and suggest that its inhibition may be useful to slow down the disease progression. Background: Immune cells significantly contribute to the progression of autosomal dominant polycystic kidney disease (ADPKD), the most common genetic disorder of the kidney caused by the dysregulation of the Pkd1 or Pkd2 genes. However, the mechanisms triggering the immune cells recruitment and activation are undefined. Methods: Immortalized murine collecting duct cell lines were used to dissect the molecular mechanism of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) activation in the context of genotoxic stress induced by Pkd1 ablation. We used conditional Pkd1 and knockout cGas-/- genetic mouse models to confirm the role of cGAS/stimulator of the interferon genes (STING) pathway activation on the course of renal cystogenesis. Results: We show that Pkd1 -deficient renal tubular cells express high levels of cGAS, the main cellular sensor of cytosolic nucleic acid and a potent stimulator of proinflammatory cytokines. Loss of Pkd1 directly affects cGAS expression and nuclear translocation, as well as activation of the cGAS/STING pathway, which is reversed by cGAS knockdown or functional pharmacological inhibition. These events are tightly linked to the loss of mitochondrial structure integrity and genotoxic stress caused by Pkd1 depletion because they can be reverted by the potent antioxidant mitoquinone or by the re-expression of the polycystin-1 carboxyl terminal tail. The genetic inactivation of cGAS in a rapidly progressing ADPKD mouse model significantly reduces cystogenesis and preserves normal organ function. Conclusions: Our findings indicate that the activation of the cGAS/STING pathway contributes to ADPKD cystogenesis through the control of the immune response associated with the loss of Pkd1 and suggest that targeting this pathway may slow disease progression.
MeSH term(s)	Animals ; Mice ; Polycystic Kidney, Autosomal Dominant/genetics ; Polycystic Kidney, Autosomal Dominant/metabolism ; TRPP Cation Channels/genetics ; TRPP Cation Channels/metabolism ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Mice, Knockout ; Disease Progression ; Interferons/metabolism ; Polycystic Kidney Diseases
Chemical Substances	TRPP Cation Channels ; Nucleotidyltransferases (EC 2.7.7.-) ; Interferons (9008-11-1)
Language	English
Publishing date	2024-01-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.0000000000000305
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Article ; Online: Kidney tissue engineering for precision medicine.

Anandakrishnan, Nanditha / Azeloglu, Evren U

Nature reviews. Nephrology

2020 Volume 16, Issue 11, Page(s) 623–624

MeSH term(s)	Animals ; Clinical Trials as Topic ; Drug Design ; Humans ; Kidney Diseases/drug therapy ; Nephrology/trends ; Precision Medicine ; Tissue Engineering/trends
Language	English
Publishing date	2020-09-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2490366-8
ISSN	1759-507X ; 1759-5061
ISSN (online)	1759-507X
ISSN	1759-5061
DOI	10.1038/s41581-020-00355-6
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Article ; Online: Computational study of biomechanical drivers of renal cystogenesis.

Ateshian, Gerard A / Spack, Katherine A / Hone, James C / Azeloglu, Evren U / Gusella, G Luca

Biomechanics and modeling in mechanobiology

2023 Volume 22, Issue 4, Page(s) 1113–1127

Abstract: Renal cystogenesis is the pathological hallmark of autosomal dominant polycystic kidney disease, caused by PKD1 and PKD2 mutations. The formation of renal cysts is a common manifestation in ciliopathies, a group of syndromic disorders caused by mutation ... ...

Abstract	Renal cystogenesis is the pathological hallmark of autosomal dominant polycystic kidney disease, caused by PKD1 and PKD2 mutations. The formation of renal cysts is a common manifestation in ciliopathies, a group of syndromic disorders caused by mutation of proteins involved in the assembly and function of the primary cilium. Cystogenesis is caused by the derailment of the renal tubular architecture and tissue deformation that eventually leads to the impairment of kidney function. However, the biomechanical imbalance of cytoskeletal forces that are altered in cells with Pkd1 mutations has never been investigated, and its nature and extent remain unknown. In this computational study, we explored the feasibility of various biomechanical drivers of renal cystogenesis by examining several hypothetical mechanisms that may promote morphogenetic markers of cystogenesis. Our objective was to provide physics-based guidance for our formulation of hypotheses and our design of experimental studies investigating the role of biomechanical disequilibrium in cystogenesis. We employed the finite element method to explore the role of (1) wild-type versus mutant cell elastic modulus; (2) contractile stress magnitude in mutant cells; (3) localization and orientation of contractile stress in mutant cells; and (4) sequence of cell contraction and cell proliferation. Our objective was to identify the factors that produce the characteristic tubular cystic growth. Results showed that cystogenesis occurred only when mutant cells contracted along the apical-basal axis, followed or accompanied by cell proliferation, as long as mutant cells had comparable or lower elastic modulus than wild-type cells, with their contractile stresses being significantly greater than their modulus. Results of these simulations allow us to focus future in vitro and in vivo experimental studies on these factors, helping us formulate physics-based hypotheses for renal tubule cystogenesis.
MeSH term(s)	Humans ; Kidney/metabolism ; Polycystic Kidney, Autosomal Dominant/genetics ; Polycystic Kidney, Autosomal Dominant/metabolism ; Polycystic Kidney, Autosomal Dominant/pathology ; Polycystic Kidney Diseases/metabolism ; Polycystic Kidney Diseases/pathology ; Mutation/genetics
Language	English
Publishing date	2023-04-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2093052-5
ISSN	1617-7940 ; 1617-7959
ISSN (online)	1617-7940
ISSN	1617-7959
DOI	10.1007/s10237-023-01704-7
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Zs.A 5966: Show issues

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Article ; Online: Open-Source System for Real-Time Functional Assessment of In Vitro Filtration Barriers.

Fallon, Tess K / Zuvin, Merve / Stern, Alan D / Anandakrishnan, Nanditha / Daehn, Ilse S / Azeloglu, Evren U

Annals of biomedical engineering

2023 Volume 52, Issue 2, Page(s) 327–341

Abstract: The integrity of the barrier between blood and the selective filtrate of solutes is important for homeostasis and its disruption contributes to many diseases. Microphysiological systems that incorporate synthetic or natural membranes with human cells can ...

Abstract	The integrity of the barrier between blood and the selective filtrate of solutes is important for homeostasis and its disruption contributes to many diseases. Microphysiological systems that incorporate synthetic or natural membranes with human cells can mimic biological filtration barriers, such as the glomerular filtration barrier in the kidney, and they can readily be used to study cellular filtration processes as well as drug effects and interactions. We present an affordable, open-source platform for the real-time monitoring of functional filtration status in engineered microphysiological systems. Using readily available components, our assay can linearly detect real-time concentrations of two target molecules, FITC-labeled inulin and Texas Red-labeled human-serum albumin, within clinically relevant ranges, and it can be easily modified for different target molecules of varying sizes and tags. We demonstrate the platform's ability to determine the concentration of our target molecules automatically and consistently. We show through an acellular context that the platform enables real-time tracking of size-dependent diffusion with minimal fluid volume loss and without manual extraction of media, making it suitable for continuous operational monitoring of filtration status in microphysiological system applications. The platform's affordability and integrability with microphysiological systems make it ideal for many precision medicine applications, including evaluation of drug nephrotoxicity and other forms of drug discovery.
MeSH term(s)	Humans ; Kidney/physiology ; Glomerular Filtration Barrier/physiology
Language	English
Publishing date	2023-10-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	185984-5
ISSN	1573-9686 ; 0191-5649 ; 0090-6964
ISSN (online)	1573-9686
ISSN	0191-5649 ; 0090-6964
DOI	10.1007/s10439-023-03378-9
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Zs.A 1018: Show issues

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Article: Modeling the Glomerular Filtration Barrier and Intercellular Crosstalk.

Ebefors, Kerstin / Lassén, Emelie / Anandakrishnan, Nanditha / Azeloglu, Evren U / Daehn, Ilse S

Frontiers in physiology

2021 Volume 12, Page(s) 689083

Abstract: The glomerulus is a compact cluster of capillaries responsible for blood filtration and initiating urine production in the renal nephrons. A trilaminar structure in the capillary wall forms the glomerular filtration barrier (GFB), composed of glycocalyx- ... ...

Abstract	The glomerulus is a compact cluster of capillaries responsible for blood filtration and initiating urine production in the renal nephrons. A trilaminar structure in the capillary wall forms the glomerular filtration barrier (GFB), composed of glycocalyx-enriched and fenestrated endothelial cells adhering to the glomerular basement membrane and specialized visceral epithelial cells, podocytes, forming the outermost layer with a molecular slit diaphragm between their interdigitating foot processes. The unique dynamic and selective nature of blood filtration to produce urine requires the functionality of each of the GFB components, and hence, mimicking the glomerular filter
Language	English
Publishing date	2021-06-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2021.689083
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Article ; Online: Good practices for building dynamical models in systems biology.

Azeloglu, Evren U / Iyengar, Ravi

Science signaling

2015 Volume 8, Issue 371, Page(s) fs8

Abstract: Dynamic models can offer deep understanding of information processing mechanisms in physiology, cell signaling, and biological regulation when they are appropriately detailed. Here, we describe some of the key aspects of the model-building process, ... ...

Abstract	Dynamic models can offer deep understanding of information processing mechanisms in physiology, cell signaling, and biological regulation when they are appropriately detailed. Here, we describe some of the key aspects of the model-building process, including proper parameterization and error analysis, as well as common mistakes, such as model-tweaking and oversimplification, which can decrease the value of the models.
MeSH term(s)	Animals ; Humans ; Models, Biological ; Systems Biology/methods
Language	English
Publishing date	2015-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aab0880
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Article ; Online: Signaling networks: information flow, computation, and decision making.

Azeloglu, Evren U / Iyengar, Ravi

Cold Spring Harbor perspectives in biology

2015 Volume 7, Issue 4, Page(s) a005934

Abstract: Signaling pathways come together to form networks that connect receptors to many different cellular machines. Such networks not only receive and transmit signals but also process information. The complexity of these networks requires the use of ... ...

Abstract	Signaling pathways come together to form networks that connect receptors to many different cellular machines. Such networks not only receive and transmit signals but also process information. The complexity of these networks requires the use of computational models to understand how information is processed and how input-output relationships are determined. Two major computational approaches used to study signaling networks are graph theory and dynamical modeling. Both approaches are useful; network analysis (application of graph theory) helps us understand how the signaling network is organized and what its information-processing capabilities are, whereas dynamical modeling helps us determine how the system changes in time and space upon receiving stimuli. Computational models have helped us identify a number of emergent properties that signaling networks possess. Such properties include ultrasensitivity, bistability, robustness, and noise-filtering capabilities. These properties endow cell-signaling networks with the ability to ignore small or transient signals and/or amplify signals to drive cellular machines that spawn numerous physiological functions associated with different cell states.
MeSH term(s)	Computational Biology ; Models, Theoretical ; Signal Transduction
Language	English
Publishing date	2015-04-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1943-0264
ISSN (online)	1943-0264
DOI	10.1101/cshperspect.a005934
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Article: Predicting individual-specific cardiotoxicity responses induced by tyrosine kinase inhibitors.

Shim, Jaehee V / Xiong, Yuguang / Dhanan, Priyanka / Dariolli, Rafael / Azeloglu, Evren U / Hu, Bin / Jayaraman, Gomathi / Schaniel, Christoph / Birtwistle, Marc R / Iyengar, Ravi / Dubois, Nicole C / Sobie, Eric A

Frontiers in pharmacology

2023 Volume 14, Page(s) 1158222

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2023-04-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1158222
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Article ; Online: HCK induces macrophage activation to promote renal inflammation and fibrosis via suppression of autophagy.

Chen, Man / Menon, Madhav C / Wang, Wenlin / Fu, Jia / Yi, Zhengzi / Sun, Zeguo / Liu, Jessica / Li, Zhengzhe / Mou, Lingyun / Banu, Khadija / Lee, Sui-Wan / Dai, Ying / Anandakrishnan, Nanditha / Azeloglu, Evren U / Lee, Kyung / Zhang, Weijia / Das, Bhaskar / He, John Cijiang / Wei, Chengguo

Nature communications

2023 Volume 14, Issue 1, Page(s) 4297

Abstract: Renal inflammation and fibrosis are the common pathways leading to progressive chronic kidney disease (CKD). We previously identified hematopoietic cell kinase (HCK) as upregulated in human chronic allograft injury promoting kidney fibrosis; however, the ...

Abstract	Renal inflammation and fibrosis are the common pathways leading to progressive chronic kidney disease (CKD). We previously identified hematopoietic cell kinase (HCK) as upregulated in human chronic allograft injury promoting kidney fibrosis; however, the cellular source and molecular mechanisms are unclear. Here, using immunostaining and single cell sequencing data, we show that HCK expression is highly enriched in pro-inflammatory macrophages in diseased kidneys. HCK-knockout (KO) or HCK-inhibitor decreases macrophage M1-like pro-inflammatory polarization, proliferation, and migration in RAW264.7 cells and bone marrow-derived macrophages (BMDM). We identify an interaction between HCK and ATG2A and CBL, two autophagy-related proteins, inhibiting autophagy flux in macrophages. In vivo, both global or myeloid cell specific HCK-KO attenuates renal inflammation and fibrosis with reduces macrophage numbers, pro-inflammatory polarization and migration into unilateral ureteral obstruction (UUO) kidneys and unilateral ischemia reperfusion injury (IRI) models. Finally, we developed a selective boron containing HCK inhibitor which can reduce macrophage pro-inflammatory activity, proliferation, and migration in vitro, and attenuate kidney fibrosis in the UUO mice. The current study elucidates mechanisms downstream of HCK regulating macrophage activation and polarization via autophagy in CKD and identifies that selective HCK inhibitors could be potentially developed as a new therapy for renal fibrosis.
MeSH term(s)	Animals ; Humans ; Mice ; Autophagy ; Fibrosis ; Inflammation/pathology ; Kidney/metabolism ; Macrophage Activation ; Mice, Inbred C57BL ; Nephritis/metabolism ; Proto-Oncogene Proteins c-hck/metabolism ; Renal Insufficiency, Chronic/pathology ; Ureteral Obstruction/metabolism
Chemical Substances	HCK protein, human (EC 2.7.10.2) ; Proto-Oncogene Proteins c-hck (EC 2.7.10.2) ; Hck protein, mouse (EC 2.7.10.2)
Language	English
Publishing date	2023-07-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-40086-3
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