Podocyte Biology and clinical applications Dr. F. Ahmadi Professor Of Nephrology TUMS

Transcription

1 Podocyte Biology and clinical applications Dr. F. Ahmadi Professor Of Nephrology TUMS

2 Proteinuria is a major healthcare problem that affects several hundred million people worldwide. Proteinuria is a cardinal sign and a prognostic marker of kidney disease, and also an independent risk factor for cardiovascular morbidity and mortality.

3 Although the glomerular endothelium, glomerular basement membrane and podocytes all contribute to the filtration barrier, the podocytes seem to be the most critical part of the filtration unit Most cases of proteinuria are associated with retraction (effacement) of podocyte foot processes, although the mechanisms of this association are not well understood

4 Podocyte injury is a major cause of marked albuminuria Podocytes are important for the maintenance of intact glomerular filtration barrier An essential role of these cells in the pathogenesis of glomerulosclerosis and progressive proteinuric kidney disease Podocyte injury and death are major factors in the initiation and progression of glomerulosclerosis.

5 Glomerular capillary wall

6 The podocyte and slit diaphragm

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8 Major Functions of the Podocyte Structural support of the capillary loop Major component of glomerular filtration barrier(gfb) to proteins Synthesis and repair of the GBM Production of growth factors Immunologic function

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10 The podocyte-gbm interface The slit diaphragm The slit diaphragm actin interface Role of TRPC6 Role of phospholipase C ε Role of MYH9 Role of the notch pathway Role of the urokinase receptor

11 The podocyte-gbm interface α3β1 integrin is the most abundant isoform However, α3β1 integrin is a major receptor for the laminin α5 chain of laminin-521 Integrin-linked kinase (ilk) has an essential role in the glomerular filtration barrier. The tetraspanin CD151 has a strong lateral interaction with integrin α3β1.

12 The slit diaphragm The slit diaphragm is formed by a complex of the plasmamembrane proteins nephrin, NEPH1 3, podocin, Fat1, VEcadherin, and P-cadherin

13 The slit diaphragm actin interface The slit diaphragm is connected to the actin cyto-skeleton via several linker proteins, including CD2AP and NCK The above data suggest that both CD2AP and NCK proteins are crucial in linking the slit diaphragm to actin

14 Podocyte foot processes

15 Genetic glomerular diseases and their associated mutated podocyte genes

16 Podocyte Responses to Injury in Disease Decrease in Podocyte Number(Podocytopenia) Podocyte Proliferation Foot-Process Effacement Altered Slit Diaphragm Integrity Production of Inflammatory Mediators

17 Mechanisms leading to proteinuria following podocyte injury

18 Causes of podocyte effacement

19 Podocyte disorders in hereditary and acquired proteinuria syndrome H. Cheng, R.C. Harris / The International Journal of Biochemistry & Cell Biology 42 (2010)

20 Illustration of the consequences of podocyte injury KI 2016

21 The glomerular filtration barrier of the kidney retains most of the circulating protein

22 Damage to podocytes can result in effacement of foot processes and the detachment or apoptosis of podocytes.

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24 Causes of FP effacement and proteinuria Changes in SD structure or function Inter-ference with the GBM or the podocyte GBM interaction Dysfunction of the podocyte actin cytoskeleton modulation of the negative surface charge of podocytes Activation of CatL-mediated proteolysis

25 Consequences of podocyte injury

26 Induction of cathepsin L in podocytes precedes FP effacement and proteinuria

27 Integrative model for the regulation of podocyte actin dynamics in health and disease

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29 Cell matrix adhesion of podocytes in physiology and disease Mutations in components that mediat podocyte matrix adhesions may cause glomerular disease characterized by GBM abnormalities, podocyte foot process effacement, and proteinuria

30 Transmembrane proteins involved in podocyte adhesion; Integrin α3β1 Integrin α2β1 Tetraspanin CD151 Vitronectin αvβ3 Dystroglycan Cell-surface HSPGs

31 Cytosolic podocyte proteins Protein tyrosine kinase 2 Integrin-linked kinase( ILK) Kindlin-2 α-actinin-4 MYO1E MYH9 GTPases (Rho, Rac, Cdc42)

32 Proteins involved in podocyte adhesion

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34 The role of lipids in podocyte biology APOL1 sequence variant in FSGS SMPDL3b has a role in the conversion of sphingomyelin to ceramide phospholipase A2(PLA2) receptor in MGN cholesterol efflux, free fatty acids and glycerophospolipids in DN

35 Lipids and lipid-related enzymes might modulate podocyte function Lipid biology is important in understanding the pathogenesis of glomerular diseases of metabolic and nonmetabolic origin Plasma membrane and intracellular lipids can modulate podocyte function irrespective of circulating lipids Therapeutic strategies that target cellular lipids, such as cholesterol and sphingolipids, might be protective in kidney disease

36 Lipids in the slit diaphragm

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38 Podocytes are susceptible to variou glomerular injuries and undergo a series of adaptive, maladaptive or catastrophic responses, depending on the severity and duration of the insult Wnt/β-catenin controls the transcription of a battery of target genes such as Snail1, MMP-7and Fsp1, and mediates podocyte dedifferentiation and mesenchymal transition, thereby inducing podocytopathy and proteinuria

39 Targeted inhibition of Wnt/β-catenin signalling by a variety of approaches preserves podocyte integrity, reduces proteinuria and ameliorates kidney damage

40 The spectrum of podocyte responses after injury

41 Wnt/ - β catening signalling is activated in the injured kidney

42 The interplay between Wnt/β-catenin signalling and WT1 dictates podocyte health and disease

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44 Podocytic target structures of commonly used drugs

45 Effects and target structures of new anti-proteinuric strategies on podocytes

46 Illustration of different drug targets in the podocyte

47 Signalling pathways activated by different drugs in podocytes

48 Injurious effects of angiotensin II on podocytes

49 Therapeutic targeting of aldosterone: a novel approach to the treatment of glomerular disease

50 Calcium, TRPC channels, and regulation of the actin cytoskeleton in podocytes: towards a future of targeted therapies

51 Immunosuppressive agents in podocytes Kidney Res Clin Pract 34 (2015) 69 75

52 Potential mechanisms of action of mycophenolic acid(mpa) In glomerulopathies Pediatr Nephrol 2016

53 World J Pediatr, Vol 11 No 1. February 15, 2015 World J PeWorld J Pediatr, Vol 11 No 1.February 15, 2015

54 Hypotheses for the pathogenesis of MCD with a central focus on podocytes CD80 expression on podocytes as a key player in the induction of proteinuria, preventing β-integrin activation(abatacept) Podocyte expressed angiopoietin-like 4 (Angptl4) as a key player in the induction of proteinuria

55 Podocyte as a novel target for therapies in minimalchange disease

56 Limitations to the hypotheses focusing on podocyte-related molecules Variety of pathogenic mechanisms contribute to the development of MCD There is still debate over whether MCD and FSGS represent different ends of the same disease Importance of the role of CD80 in MCD has been proposed mainly by one group Most patients with genetic FSGS did not benefit from CsA

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58 Monoclonal antibodies might help to elucidate the pathogenesis ofpodocytopathies and might also be useful for treatment of these diseases Rituximab therapy has been associated with remission in cases of minimal change nephropathy and focal segmental glomerulosclerosis

59 Biologic therapies and the immune system

60 Potential targets of immunosuppressive agents in podocytes

61 Conclusions A crucial structure for podocyte maintenance is the actin cytoskeleton. It is apparent that many of the drugs currently used to treatment glomerular diseases have direct effects on the podocytes and their cytoskeleton, but are still not podocyte-specific Some drugs have direct side effects on podocytes, causing proteinuria and loss of podocytes from the GBM The discovery of novel genes and signalling pathways involved in glomerular diseases will facilitate the future development of podocyte-specific drugs

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