The glomerular filtration barrier consists of three layers - the fenestrated endothelial cell layer, the thick glomerular basement membrane (GBM), and the podocyte foot processes and slit diaphragm. It allows filtration of water and small solutes while preventing the loss of proteins and cells. The GBM is negatively charged and contains type IV collagen and laminin, forming a size and charge selective barrier. Podocytes play a key role through their foot processes and slit diaphragm attachment to the GBM. Vascular endothelial growth factor (VEGF) produced by podocytes regulates endothelial cell permeability and maintenance of the filtration barrier.

1. GLOMERULAR FILTRATION BARRIER
• TOPICS
• ANATOMY OF GLOMERULAR FILTRATION BARRIER
• PHYSIOLOGY
• CLINICAL IMPLICATIONS

4. • Filtration barrier:
Fenestrated capillary endothelium
Glomerular basement membrane
filtration slit or slit diaphragm
2 MODELS
PORE MODEL
ELECTROKINETIC MODEL

5. ENDOTHELIAL CELLS
• The glomerular capillaries are lined by a thin fenestrated Endothelium
• Under normal conditions, the formed elements of the blood,
including erythrocytes, leukocytes, and platelets, do not gain access
to the subendothelial space.
• The endothelium contains pores or fenestrae that range from 70 to
100 nm in diameter
• Non fenestrated endothelium has no role

7. • The glomerular endothelium is covered by a glycocalyx layer
• The glycocalyx also fills the endothelial fenestrae forming “sieve
plugs,” the exact function of which is unknown.
• The glycocalyx consists of membrane-bound proteoglycans (syndecan
and glypican) with attached glycosaminoglycans (GAGs), secreted
glycoproteins (perlecan and versican), and secreted GAGs
(hyaluronan), which provide a negative charge.
• Endogenous albumin is largely confined to the glomerular capillary
lumen and does not pass through the endothelium

8. Signaling between glomerular cells is critical for the
development and maintenance of the filtration barrier.
VEGF is synthesized by podocytes (glomerular visceral epithelial
cells) and is an important regulator of microvascular
permeability.
VEGF increases endothelial cell permeability and induces the formation of
endothelial fenestrations.
VEGF-A is the best characterized podocyte growth factor, and its principal
receptor is VEGFR2, expressed on endothelial cells

9. Podocyte-specific alterations of VEGF-A have demonstrated that it is
required for normal differentiation of glomerular endothelial cells
Drug inhibition of VEGF-A in patients or podocyte-specific deletion of
VEGF-A in adult mice results in severe glomerular endothelial injury
and thrombotic microangiopathy.
Thus, VEGF produced by podocytes plays a critical role in the
differentiation and maintenance of glomerular endothelial cells and is
an important regulator of endothelial cell permeability

10. • Thus, VEGF produced by podocytes plays a critical role in the
differentiation and maintenance of glomerular endothelial cells and is
an important regulator of endothelial cell permeability
• VEGF IS THE MAIN MOLECULE
• SURVIVAL/DAMAGE/PROLIFERATION/MAINTENACE

14. GLOMERULAR BASEMENT MEMBRANE
• By transmission electron microscopy, the GBM is composed
of a central dense layer, the lamina densa, and two thinner
more electron-lucent layers, the lamina rara externa and the
lamina rara interna
• Like other basement membranes in the body, the GBM is composed
primarily of type IV collagen, laminin, nidogen (entactin), and
heparan sulfate proteoglycans (HSPGs).
• DIFFERENCES BETWEEN GBM AND OTHER TWO LAYERS

15. 2.9

17. Compared with other basement membranes, the
GBM is thicker, likely at least in part from fusion of endothelial
and epithelial basement membranes during development.
Type IV collagen consists of six chains, α1(IV) through
α6(IV).
Three α(ΙV) chains self-associate intracellularly to
form triple helical molecules called protomers

18. Three types of promoters are formed: α1α2α1, α3α4α5, and α5α6α5.
Upon secretion into the extracellular space, the protomers
self-associate via their amino- and carboxy-terminal domains
to form polymerized networks.

19. The α3α4α5(IV)-α3α4α5(IV) network predominates
in the GBM, whereas the α1α2α1(IV)-α5α6α5(IV)
network is in Bowman’s capsule.
Whereas α1α2α1(IV) protomers are synthesized from both endothelial
cells and podocytes, α3α4α5(IV) protomers are secreted only by
podocytes.

20. Ultrastructural tracer studies provided evidence to suggest that the GBM
constitutes both a size-selective and a charge-selective barrier.
Additional studies revealed a lattice of anionic sites with a spacing
between them of approximately 60 nm throughout
the lamina rara interna and lamina rara externa.
The anionic sites in the GBM consist of heparan sulfate GAG
side chains of the proteoglycans rich in heparan sulfate.
Role is minimal
Importance of laminin beta 2 is increasing recently

21. PODOCYTES AND THEIR ROLE
Podocytes (visceral epithelial cells) are the largest cells in
the glomerulus
• Mature podocytes are terminally differentiated
• They have a prominent cell body containing nuclei, endoplasmic
reticulum, Golgi apparatus, and an endocytic–lysosomal system
• The gap between adjacent foot processes is bridged by a thin
structure called the filtration slit diaphragm.

22. • Podocytes have an elaborate cytoskeleton that underlies their shape,
stability, adhesion, and response to stress.
• Large numbers of microtubules and intermediate filaments (vimentin)
are present in the cell body and primary processes,whereas actin
filaments are especially abundant in the foot processes
The filtration slits have a constant width of approximately 30 to 40 nm
thus the SD has to connect the FPs over a considerable distance

23. The transmembrane proteins that establish the slit diaphragm (SD) and its
connection to the actin cytoskeleton of the FPs include nephrin, P-cadherin,
FAT1, NEPH 1-3,podocin, and CD2AP, among others
They also include receptors for cyclic guanosine monophosphate (cGMP)
signaling, stimulated by natriuretic peptides (atrial natriuretic peptide [ANP],
brain natriuretic peptide [BNP], and C-type natriuretic peptide [CNP]) and
nitric oxide; receptors for cyclic adenosine monophosphate (cAMP) signaling
stimulated by prostaglandin E2 (PGE2), dopamine, VEGF, isoproterenol,
parathyroid hormone (PTH), PTH-related peptide; and receptors for Ca2+
signaling stimulated by numerous ligands, including angiotensin II,
acetylcholine, PGF2, arginine vasopressin (AVP), adenosine triphosphate
(ATP), endothelin, and histamine.
• Among the transient receptor potential (TRP) cation
channels, TRPC5 and TRPC6 have received much attention

24. • FILTRATION PRESSURE
• FILTRATION FLOW
FPs, which need their cytoskeleton to continually adapt their pattern of
attachment to the GBM would simultaneously function as contractile
pericyte-like processes, counteracting the expansion of the GBM by
increasing their tone.
Consequently,it may be concluded that the principal burden for
counteracting transmural pressure gradients (i.e., for developing wall
tension) falls instead on the GBM.
• FOOT PROCEESSES ,SLIT DIAPHRAGM AND GMB ACT SYNERGESTICALLY

25. • Podocytes and their processes
• Foot processes or pedicels
• Filtration slit or slit pore
• Slit diaphragm/modified adherens junction
• Cytoskeleton(microtubules and intermediate filaments like vimentin
and desmin)
• Actin myosin interactions

28. SUMMARY

29. • Size of the particles
• <4 nm-freely filtered
• >8 nm- never filtered
• 4-8 nm-depends on charge
Low molecular weight(<70000 daltons),water are filtered
Plasma proteins like albumin,globulins,calacium,fatty acids are not
filtered

31. • Type 4 collagen and laminin are the main component of GBM.
• PAS stains mesangial matrix, GBM, tubular basement membrane and
hyaline deposits.
• The 3 layers of glomerular capillary membrane acts as filtration barrier and
ultrafiltrate is formed.
• GBM has negative charge, hence negatively charged bodies are not filtered.
For a give molecular radius, the filtration is positive
molecules>neutral>negative.

34. THANK YOU