20. Glomerular Podocyte and the Podocyte Depletion Hypothesis

stages of depletion

- at a depletion of 0-20% there is no effect - 21-40% = low level proteins detected in urine, adhesions and FSGS however renal function normal (will become worse though) - >40% = global sclerosis, high level of proteinuria and impaired renal function - was found by expressing a diphtheria receptor on podocytes so when exposed to toxin at different concentrations podocytes were eliminated

glomerular cell numbers in adults and children

- in adults compared to children there are more podocytes, they are larger, also greater variation - large adult glomeruli contain more podocytes than smaller ones (don't know if acquired it or if born with it) - 20% increase in podocyte number after 2 months

Filtration slits

-20-30 nm wide -Bridged by thin diaphragm 4-6 nm thick -Zipper-like arrangement of cross-bridges -Pores are 4 x 14 nm -approx size of albumin

Podocyte cell body

-Contains large, complexly shaped nucleus -Numerous microtubules and microfilaments -Abundant RER, Golgi complexes, lysosomes

Podocyte foot processes

-Interdigitate -Contain dense matrix of actin, myosin, alpha actinin -Virtually devoid of microtubules and vimentin -Thick negatively charged surface glycocalyx rich in sialic acid and HSPG

Glomerular diseases can be categorised into

-those that primarily involve the kidney (primary glomerular diseases) -those in which kidney involvement is part of a systemic disorder (secondary glomerular diseases; eg. diabetic nephropathy) •While some glomerular disorders consistently cause a specific syndrome (eg. minimal change disease resulting in nephrotic syndrome), most disorders are capable of causing features of both nephrosis and nephritis

Nephrosis

9aka nephrotic syndrome) -characterised by massive proteinuria (> 3.5 g/24 hrs) associated with oedema, hyperlipidaemia, hypoproteinaemia and other metabolic disorders.

functions of podocytes

Functions -Components of the glomerular filtration barrier -Synthesise components of the glomerular basement membrane (GBM) •Main source of heparan sulphate proteoglycans (HSPGs) •Also synthesise collagen type IV, fibronectin, MMPs and TIMPs -Synthesise VEGF1 which plays a key role in endothelial cell formation and maintenance

Podocyte Depletion Hypothesis via

a. podocyte loss (necrosis apoptosis detachment) b. glomerular enlargement (podocytes don't enlarge, can't cover SA) c. podocyte phenotype switch (becomes squamous and flat without foot processes) this leads to effective podocyte depletion --> glomerulosclerosis --> progression to ESKD

Nephritis

features include haematuria, proteinuria and cellular proliferation of the glomerulus.

Podocyte Depletion in Human Pathology

•Alport Syndrome •Hypertensive nephrosclerosis •IgA nephropathy •Obesity-related glomerulopathy •Transplant glomerulopathy •Type 1 diabetes •Type 2 diabetes

Mesangial Cells

•Mesangial cells and mesangial matrix form the glomerular mesangium •The mesangium constitutes the central core of the glomerulus to which capillaries are attached •Highly proliferative and contractile cells •Elongated cytoplasmic processes •Remodel mesangial matrix. Secrete: -Components of the extracellular matrix -Growth factors/cytokines -e.g. TGF-β1 -Matrix metalloproteinases (MMPs) -TIMPs -Collagenases -Reactive oxygen species •Regulate glomerular blood flow

Endothelial Cells

•Nuclei and organelles located in axial region •Extensive network of intermediate filaments and microtubules •Fenestrae (pores, holes) -Numerous (occupy 20% of total capillary surface area) -In cell cytoplasm -not between cells -Open -no visible diaphragm -Glomerular capillaries are 100x more permeable to water than muscle capillaries. The leakiest capillaries in the body.

Podocytes

•Podocytes are also known as : -Glomerular epithelial cells -Visceral glomerular epithelial cells •Mostly incapable of mitosis under normal conditions. This can lead to pathology ("podocyte depletion hypothesis") •Can proliferate in certain pathological settings -eg. HIV associated nephropathy (HIVAN) •Consist of cell body, major cytoplasmic processes and foot processes

Glomerulus and Renal Corpuscle

•The glomerulusis the filtration apparatus of the kidney •Each glomerulus consists of three resident cell types: -Endothelial cells -Mesangial cells -Podocytes •Renal corpuscleconsists of -Glomerulus -Urinary space -Bowman's capsule (parietal epithelial cells)

Glomerular Pathology

•The underlying cause of most glomerular diseases remains unknown. •The glomerulus can be damaged by: -Generalised vascular disease (eg. hypertension, vasculitis, diabetes mellitus) -Immunological disorders (eg. where immune complexes are deposited in various regions of the glomerular capillary walls) -Deposition of foreign material (eg. amyloid) •Infectious agents, autoimmunity, drugs, inherited disorders and environmental agents all involved in glomerular pathology. •The podocyte depletion hypothesis has emerged in recent years as a new unifying principle in glomerular pathology