Intraglomerular crosstalk elaborately regulates podocyte injury and repair in diabetic patients: insights from a 3D multiscale modeling study.
Podocytes are mainly involved in the regulation of glomerular filtration rate (GFR) under physiological condition. Podocyte depletion is a crucial pathological alteration in diabetic nephropathy (DN) and results in a broad spectrum of clinical syndromes such as protein urine and renal insufficiency. Recent studies indicate that depleted podocytes can be regenerated via differentiation of the parietal epithelial cells (PECs), which serve as the local progenitors of podocytes. However, the podocyte regeneration process is regulated by a complicated mechanism of cell-cell interactions and cytokine stimulations, which has been studied in a piecemeal manner rather than systematically. To address this gap, we developed a high-resolution multi-scale multi-agent mathematical model in 3D, mimicking the in situ glomerulus anatomical structure and micro-environment, to simulate the podocyte regeneration process under various cytokine perturbations in healthy and diabetic conditions. Our model showed that, treatment with pigment epithelium derived factor (PEDF) or insulin-like growth factor-1 (IGF-1) alone merely ameliorated the glomerulus injury, while co-treatment with both cytokines replenished the damaged podocyte population gradually. In addition, our model suggested that continuous administration of PEDF instead of a bolus injection sustained the regeneration process of podocytes. Part of the results has been validated by our in vivo experiments. These results indicated that amelioration of the glomerular stress by PEDF and promotion of PEC differentiation by IGF-1 are equivalently critical for podocyte regeneration. Our 3D multi-scale model represents a powerful tool for understanding the signaling regulation and guiding the design of cytokine therapies in promoting podocyte regeneration.
Center for Bioinformatics and Systems Biology, Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Hua
H
Tan
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.|Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Hualin
H
Yi
Center for Bioinformatics and Systems Biology, Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Weiling
W
Zhao
Department of Physiology, University of Oklahoma College of Medicine, Oklahoma, OK 73104, USA.
Jian-Xing
JX
Ma
Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Yuanyuan
Y
Zhang
Center for Bioinformatics and Systems Biology, Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.|College of Computer Science and Software Engineering, Shenzhen University, Shenzhen, China.
Xiaobo
X
Zhou
D000465:Algorithms; D015415:Biomarkers; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008954:Models, Biological; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
D015415:Biomarkers
diabetic nephropathy; glomerulus; multi-agent model; multi-scale model; podocyte regeneration
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