The document discusses the important role of the podocyte cytoskeleton in renal physiology and disease. Podocytes are cells that wrap around capillaries in the glomerulus and their cytoskeleton, composed of proteins like nephrin, podocin, and alpha-actinin-4, helps maintain glomerular filtration and the slit diaphragm barrier. Dysfunctions in these proteins can lead to renal diseases like focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy by disrupting podocyte structure and function. The podocyte cytoskeleton is therefore a key target for understanding the pathogenesis and potential treatment of proteinuric kidney diseases.

1. ROLE OF PODOCYTE CYTOSKELETON IN
PHYSIOLOGY AND RENAL DISEASES
Presented by:
UDDANDI SATYA KARTHIK
RT/2019/617
DEPT. OF REGULATORY TOXICOLOGY
Under guidance of:
Dr. ASHUTOSH KUMAR
HEAD OF DEPARTMENT
DEPT. OF PHARMACOLOGY & TOXICOLOGY
NIPER HYDERABAD
National Institute of Pharmaceutical Educational Education and Research

2.  WHAT ARE PODOCYTES?
 Cells that wrap around capillaries of the glomerulus
 Make up the epithelial lining of Bowman's capsule
 visceral epithelial cells
 FUNCTIONS:
 They are:
 GBM-turnover
 Support of the capillary tuft
 Regulation of glomerular filtration
 Immunological functions
INTRODUCTION
TEM view of podocytes in between the capillary profiles ( C )
1. Reiser J and Altintas MM. Podocytes , F1000 Research 2016, (F1000 Faculty Rev):114
2. Peter Mundel , Wilhelm Kriz,Structure and function of podocytes: an update, Anat Embryol (1995) 192:385-397
INTERDIGITATING
FOOT PROCESSES
PODOCYTE
CELLBODY
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3. ULTRA STRUCTURE OF A PODOCYTE
FOOT PROCESS
GBM
ENDOTHELIUM
SLIT DIAPHRAGM
PODOCYTE CELLBODY
TRPC6 CD2AP PODOCALYXIN
ACTIN
α-ACTININ-4
SYNAPTOPODIN
NEPHRIN
SLIT DIAPHRAGM
Kirk N. Campbell et al;Protecting Podocytes: A Key Target for Therapy of Focal Segmental Glomerulosclerosis; American Journal of Nephrology, 2018;47(suppl 1):14–29
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PODOCIN

4. IMPORTANCE OF PODOCYTE CYTOSKELETON
 Maintains filtration
 Podocyte shape and stability
 Foot processes increase filtration surface
 Attachment of podocyte to GBM
 Provide structural stability to the glomerular tuft
Dong Sun et al., Relationship between Urinary Podocytes and Kidney Diseases; Renal Failure, 34(3): 403–407, (2012)
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5. PODOCYTE SPECIFIC CYTOSKELETON
PROTEINS
Essential role in preventing proteinuria
Important target in the pathogenesis of renal disease.
Mutations in the NPHS1 gene, which codes for nephrin, cause the most severe form of congenital
nephrotic syndrome
NEPHRIN
CYTOSKELETON
REARRANGEMENT
 NEPHRIN:
Gavin I. Welsh and Moin A. Saleem ,The podocyte cytoskeleton—key to a functioning glomerulus in health and disease , Nephrol. 8, 14–21 (2012);
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6. Podocin localizes to lipid microdomains in the slit diaphragm where it co-localizes with nephrin.
Clusters and regulates the ion channel TRPC6
 Serve as a scaffold
 PODOCIN:
PODOCIN
Gavin I. Welsh and Moin A. Saleem ,The podocyte cytoskeleton—key to a functioning glomerulus in health and disease , Nephrology ,8, 14–21 (2012); 6

7.  SYNAPTOPODIN:
Synaptopodin was found to interact with a-actinin-4
Promotes formation of actin fibers
Helps in stabilization of the podocyte actin cytoskeleton and protection from proteinuria
SYNAPTOPODIN
7
Xuefei Tian et.al.;Targeting the podocyte cytoskeleton: from pathogenesis to therapy in proteinuric kidney disease; Nephrology Dialysis Transplant (2016) 31: 1577–1583

8.  PHALLADIN:
 In Stress fiber formation
 Co-localized with actin of podocytes
 N-terminal half of palladin helps in forming focal adhesions
 C-terminal half shows only a less cytosolic staining, but a very intense staining of the nucleus
PHALLADIN ACTIN PHALLADIN+ACTIN
Nicole Endlich et al.;Palladin is a dynamic actin-associated protein in podocytes, Kidney International (2009) 75, 214–226
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9.  ΑLPHA-ACTININ-4:
 Normal podocyte adhesion , regulation of transcription
 Involved in binding actin to the membrane
α-ACTININ-4
9Gavin I. Welsh and Moin A. Saleem ,The podocyte cytoskeleton—key to a functioning glomerulus in health and disease , Nephrology ;8, 14–21 (2012);

10. RENAL DISEASES DUE TO PROTEIN DYSFUNCTION
FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) :
 Glomerualar leision, marked proteinuria and podocyte injury.
 Podocyte loss is the key event
 Mutations in the genes encoding Nephrin , CD2-associated protein , Podocin , α-actinin-4
GLOMERULAR LESION
10Agnes B. Fogo et al.; Causes and pathogenesis of focal segmental glomerulosclerosis ; Nephrology(2015) 9: 15-19

11. PROGRESSION OF FSGS TO ESRD
CYTOSKELETON
INSTABILITY
MECHANICAL STRESS
HYPERFILTRATION
GLOMERULAR
HYPERTROPY
INFLAMMATORY
RESPONE
Monocyte
Macrophage
T cell
CYTOKINE RELEASE
TGF-β,VEGF,PDGF
ANGIOTENSIN
RELATIVE
PODOCYTE LOSS
COLLAGEN MATRIX
DEPOSITION AND
FIBROSIS
Endiothelial cell
proliferation
Tubular
inflammation
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Kimberly Reidy et al.,Pathophysiology of focal segmental glomerulosclerosis, Pediatric Nephrology (2007) 22:350–354

12.  DIABETIC NEPHROPATHY
Chronic loss of kidney function occurring in those with diabetes mellitus characterized by:
 Persistent albuminuria (>300 mg/day)
 Progressive decline in GFR
 Elevated arterial blood pressure
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HIGH GLUCOSE
HAEMODYNAMIC
ALTERATIONS
LOSS OF PODOCYTELOSS OF NEPHRIN
AND PODOCIN
IMPAIRED
PODOCYTE
INTEGRITY
METABOLIC
STRESS
PROTEINURIA
RENAL INJURY
Gavin I. Welsh and Moin A. Saleem ,The podocyte cytoskeleton—key to a functioning glomerulus in health and disease , Nephrology; 8, 14–21 (2012)

13. 13
CONTD…
TGF-β
formation
APOPTOSIS
Local RAS
Podocyte stretch
Angiotensin
receptor
ANGIOTENSIN-II
Gavin I. Welsh and Moin A. Saleem ,The podocyte cytoskeleton—key to a functioning glomerulus in health and disease , Nephrology. 8, 14–21 (2012);
HYPERGLYCEMIA HAEMODYNAMIC
STRESS

14.  MINIMAL CHANGE DISEASE:
⮚ The three hallmarks of minimal change disease:
 Loss of podocyte foot processes
 Vacuolation
 Appearance of microvilli
Direct stimulation of
podocytes
Viral Bacterial
Allergen
T cell cytokines(IL-13)
HEALTY
PODOCYTE
Ineffective censoring of
podocyte CD80 due to
impaired podocyte
autoregulation
Reduced TGF-β response
CD80 expression
causes podocyte injury
Sustained podocyte
injury causes MCD
14Samuel Mon-Wei Yu et.al.,(2018) Proteinuric Kidney Diseases: A Podocyte’s Slit Diaphragm and Cytoskeleton Approach. Frontiers in Medicine 5:221.

15. SUMMARY
The podocyte cytoskeleton form the basis for the major renal functions such as glomerular
filtration and barrier to macromolecules
Several of the aforementioned proteins such as nephrin and podocin have been detected in
urine in disease conditions such as diabetic renal disease and focal glomerularsclerosis
The proteins can be used as major diagnostic markers in serval renal diseases
As several signalling pathways are interlinked with the cytoskeleton proteins, indirect targeting
of these signalling pathways preserve the podocyte structure and function
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