Role of Podocyte Injury in Glomerulosclerosis

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Abstract

Finding new therapeutic targets of glomerulosclerosis treatment is an ongoing quest. Due to a living environment of various stresses and pathological stimuli, podocytes are prone to injuries; moreover, as a cell without proliferative potential, loss of podocytes is vital in the pathogenesis of glomerulosclerosis. Thus, sufficient understanding of factors and underlying mechanisms of podocyte injury facilitates the advancement of treating and prevention of glomerulosclerosis. The clinical symptom of podocyte injury is proteinuria, sometimes with loss of kidney functions progressing to glomerulosclerosis. Injury-induced changes in podocyte physiology and function are actually not a simple passive process, but a complex interaction of proteins that comprise the anatomical structure of podocytes at molecular levels. This chapter lists several aspects of podocyte injuries along with potential mechanisms, including glucose and lipid metabolism disorder, hypertension, RAS activation, micro-inflammation, immune disorder, and other factors. These aspects are not technically separated items, but intertwined with each other in the pathogenesis of podocyte injuries.

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Most cited references 170

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Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes.

D Laybutt, A Preston, M. C. Akerfeldt … (2007)

Increased lipid supply causes beta cell death, which may contribute to reduced beta cell mass in type 2 diabetes. We investigated whether endoplasmic reticulum (ER) stress is necessary for lipid-induced apoptosis in beta cells and also whether ER stress is present in islets of an animal model of diabetes and of humans with type 2 diabetes. Expression of genes involved in ER stress was evaluated in insulin-secreting MIN6 cells exposed to elevated lipids, in islets isolated from db/db mice and in pancreas sections of humans with type 2 diabetes. Overproduction of the ER chaperone heat shock 70 kDa protein 5 (HSPA5, previously known as immunoglobulin heavy chain binding protein [BIP]) was performed to assess whether attenuation of ER stress affected lipid-induced apoptosis. We demonstrated that the pro-apoptotic fatty acid palmitate triggers a comprehensive ER stress response in MIN6 cells, which was virtually absent using non-apoptotic fatty acid oleate. Time-dependent increases in mRNA levels for activating transcription factor 4 (Atf4), DNA-damage inducible transcript 3 (Ddit3, previously known as C/EBP homologous protein [Chop]) and DnaJ homologue (HSP40) C3 (Dnajc3, previously known as p58) correlated with increased apoptosis in palmitate- but not in oleate-treated MIN6 cells. Attenuation of ER stress by overproduction of HSPA5 in MIN6 cells significantly protected against lipid-induced apoptosis. In islets of db/db mice, a variety of marker genes of ER stress were also upregulated. Increased processing (activation) of X-box binding protein 1 (Xbp1) mRNA was also observed, confirming the existence of ER stress. Finally, we observed increased islet protein production of HSPA5, DDIT3, DNAJC3 and BCL2-associated X protein in human pancreas sections of type 2 diabetes subjects. Our results provide evidence that ER stress occurs in type 2 diabetes and is required for aspects of the underlying beta cell failure.

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TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function.

Jochen Reiser, Krishna Polu, Clemens Möller … (2005)

Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.

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Podocyte injury and its consequences.

Michio Nagata (2016)

Podocytes maintain the glomerular filtration barrier, and the stability of this barrier depends on their highly differentiated postmitotic phenotype, which also defines the particular vulnerability of the glomerulus. Recent podocyte biology and gene disruption studies in vivo indicate a causal relationship between abnormalities of single podocyte molecules and proteinuria and glomerulosclerosis. Podocytes live under various stresses and pathological stimuli. They adapt to maintain homeostasis, but excessive stress leads to maladaptation with complex biological changes including loss of integrity and dysregulation of cellular metabolism. Podocyte injury causes proteinuria and detachment from the glomerular basement membrane. In addition to "sick" podocytes and their detachment, our understanding of glomerular responses following podocyte loss needs to address the pathways from podocyte injury to sclerosis. Studies have found a variety of glomerular responses to podocyte dysfunction in vivo, such as disruption of podocyte-endothelial cross talk and activation of podocyte-parietal cell interactions, all of which help us to understand the complex scenario of podocyte injury and its consequences. This review focuses on the cellular aspects of podocyte dysfunction and the adaptive or maladaptive glomerular responses to podocyte injury that lead to its major consequence, glomerulosclerosis.

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Author and article information

Contributors

Bi-Cheng Liu: +86862583262422 , liubc64@163.com

Hui-Yao Lan: hylan@cuhk.edu.hk

Lin-Li Lv: +868613770603746 , lvlinli@seu.edu.cn

Kun-Ling Ma: klma05@163.com

Journal

Journal ID (publisher-id): 978-981-13-8871-2

Journal ID (doi): 10.1007/978-981-13-8871-2

Journal ID (nlm-ta): Renal Fibrosis: Mechanisms and Therapies

Title: Renal Fibrosis: Mechanisms and Therapies

ISBN (Print): 978-981-13-8870-5

ISBN (Electronic): 978-981-13-8871-2

Publication date (Electronic): 19 June 2019

Publication date Collection: 2019

Volume: 1165

Pages: 195-232

Affiliations

[6 ]GRID grid.263826.b, ISNI 0000 0004 1761 0489, Zhongda Hospital, Southeast University School of Medicine, , Southeast University, ; Nanjing, Jiangsu China

[7 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, , Chinese University of Hong Kong, ; Hong Kong, Hong Kong

[8 ]GRID grid.263826.b, ISNI 0000 0004 1761 0489, Zhongda Hospital, Southeast University School of Medicine, , Southeast University, ; Nanjing, Jiangsu China

GRID grid.263826.b, ISNI 0000 0004 1761 0489, Institute of Nephrology, Zhong Da Hospital, , Southeast University School of Medicine, ; Nanjing, China

Article

Publisher ID: 10

DOI: 10.1007/978-981-13-8871-2_10

PMC ID: 7120923

PubMed ID: 31399967

SO-VID: bcc0acbb-c89c-4152-9012-70bf9bcbb5c0

License:

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