- The typical cell comprises a nucleus and cytoplasm, separated by the nuclear membrane
- The cytoplasm is separated from interstitial fluid by the cell membrane
- The different substances making up a cell are termed its “protoplasm” and include:
- water (usually 70%-85%)
- electrolytes – chiefly potassium, magnesium, phosphate, sulphate, bicarbonate, and a little sodium, chloride and calcium
- proteins (usually 10%-20%) – structural and globular, including enzymes
- lipids (usually 2%) – particularly phospholipids, cholesterol, triglycerides, neutral fats
- carbohydrates (usually 1%) – usually as glycogen
- The cell and its organelles are surround by membranes composed of lipids and proteins
- these include the cell membrane, nuclear membrane, and membranes of the ER, mitochondria, lysosomes and Golgi apparatus
- each prevents free movement of water and water-soluble substances between cell compartments
- The cell membrane is a lipid bilayer with inserted proteins
- the lipid bilayer is mostly phospholipids and cholesterol
- it is permeable to lipid-soluble substances, but is a major barrier to water-soluble substances such as ions
- integral proteins protrude through the membrane, while peripheral proteins are attached to the inner surface
- many integral proteins form structural channels, or carrier proteins
- peripheral proteins are usually enzymes
- the membrane is studded with glycoproteins, which are thought to repel other negatively charged molecules, allow attachment to some other cells and act as receptors for binding hormone
- The ER synthesizes substances in the cell
- aided by a large surface area
- materials made include proteins, carbohydrates, lipids, lysosomes, peroxisomes, and secretory granules
- lipids are made within the ER wall
- proteins are made by mRNA attaching to ribosomes on the outer surface of the ER
- The Golgi apparatus is prominent in secretory cells
- synthesis of lysosomes, secretory vesicles and other cytoplasmic inclusions
- transport vesicles are pinched-off bits of ER which then fuse with the Golgi apparatus
- Lysosomes provide the cell with a digestive system
- small round vesicles containing digestive enzymes
- usually cordoned-off by a non-reactive membrane
- Mitochondria release energy in the cell
- via the citric acid cycle and oxidative enzymes, producing ATP
- self-replicative and almost certainly originally symbiotic
- The nucleus acts as a control centre of the cell and contains large amounts of DNA
- separated from the cytoplasm by a nuclear envelope, pierced by several thousand pores
- most also contain one or more nucleoli, which do not have membranes; these contain large amounts of RNA, and are enlarged in cells actively synthesizing proteins
Ingestion by the Cell – Endocytosis
- Small particles enter the cell through diffusion or active transport. Very large particles enter by endocytosis, either pinocytosis or phagocytosis
- Pinocytosis is the ingestion of small globules of extracellular fluid, forming minute vesicles in the cytoplasm
- Phagocytosis is the ingestion of large particles such as bacteria, cells, and bits of degenerating tissue
- Substances so absorbed are digested in the cell by lysosomes. The products of digestion are small amino acids, lipids, glucose, phosphate
Synthesis of Cellular Structures
- The synthesis of most structures begins in the ER. The rough ER is so named because large numbers of ribosomes attach to the outer surface. Small ER vesicles continually break off from the smooth ER and migrate to the Golgi apparatus.
Extraction of Energy by Mitochondria
- Almost all oxidative reactions occur inside mitochondria and the energy released is in the form of ATP. ATP has two very labile high-energy phosphate bonds (12,000 calories per mole)
- Most of the ATP produced in cells is made by mitochondria. About 5% is made by glycolysis, the rest by the citric acid cycle. The process is called the “chemosmotic mechanism”
- ATP is used for many cellular functions, particularly membrane transport (Na-K-ATPase), synthesis of chemical compounds, and mechanical work
Locomotion and Ciliary Movements by Cells
- Amoeboid locomotion is the movement of an entire cell in relation to its surroundings (eg. a white blood cell through tissues). It begins with protrusion of a pseudopodium from one end of the cell, with continual exocytosis, and continual endocytosis of the membrane at the mid and rear portions of the cell.
- Two effects are essential to forward movement: attachment of the pseudopodium, and adequate energy for the movement. In the cytoplasm are molecules of the protein actin, which polymerize to form a filamentous network that contracts on binding to another protein such as myosin.
- Amoeboid movement is initiated usually by a chemotactic factor. The process is called chemotaxis.
- Ciliary movement is a whip-like movement of cilia on the surface of cells (only in the respiratory tract, and in the uterine tubules). The mechanism is not known.
Genetic Control of Cell Function
- Cell genes control protein synthesis. Each gene is a double-stranded helical molecule of DNA that controls the formation of RNA. RNA spreads through the cell to control the formation of a specific protein.
- Nucleotides are organized to form two strands of DNA bound loosely to each other. There are three building blocks: phosphoric acid, deoxyribose (a sugar), and four nitrogenous bases (two purines: adenine and guanine; two pyrimidines, thymine and cytosine). Adenine always bonds with thymine, and guanine always bonds with cytosine.
- The genetic code consists of triplets of bases. Each is called a code word. These determine the sequence of amino acids added to the protein.
- DNA code is transferred to RNA code by the process of transcription. It occurs in the nucleus, where each DNA code word forms a complementary RNA triplet called a codon. The basic building blocks are almost the same except ribose replaces deoxyribose, and uracil replaces thymine.
- The next step is the activation of the nucleotide, with the addition of two phosphate radicals derived from ATP. It makes available large amounts of energy to promote the reactions that add each new RNA nucleotide to the end of the RNA chain.
- The DNA strand is used as a template to assemble the RNA molecule from activated nucleotides, under the influence of the enzyme RNA polymerase.
- There are three different types of RNA:
- mRNA, carries the genetic code to the cytoplasm to control the formation of proteins
- rRNA, which along with proteins forms the ribosomes, the molecules in which proteins are actually assembled
- tRNA, which transports activated amino acids to the ribosomes – 20 types for 20 amino acids
- The operons of the DNA strand control biochemical synthesis and are activated by the promoter. The operon is controlled by a repressor and an activator operator, and through negative feedback by the cell product. I have no idea what this paragraph means.
The DNA Genetic System
- With the exception of some very long-lived cells (eg. nerve cells), most cells need to be able to reproduce their own cell type.
- Reproduction begins with replication of the DNA. As they are replicated, the DNA strands are repaired and proofread. Mistakes (mutations) rarely escape enzymes that cut out defective bits and replace them with appropriate complementary nucleotides.
- Entire chromosomes (46, 23 pairs) are replicated. In addition to the DNA, there is a fair bit of protein as histones, molecules around which the DNA is coiled to pack it in. The two newly-formed chromosomes remain temporarily attached to each other at a point called the centromere, near the centre. The duplicated but still-attached chromosomes are called chromatids.
- This is the process by which the cell splits into two new daughter cells.
- Two pairs of centrioles, small structures close to one pole of the nucleus, begin to move apart. Microtubules grow radially away from each of the centriole pairs, forming a spiny star called the aster at each end of the cell. The complex of microtubules between the pairs is called the spindle, and the entire set of microtubules plus the pairs of centrioles the mitotic apparatus.
- Prophase is the beginning of mitosis – while the spindle is forming, the chromosomes become condensed into defined chromosomes
- Prometaphase is the stage at which microtubular spines puncture and fragment the nuclear envelope, and microtubules become attached to the chromatids at the centromere
- Metaphase is the stage at which the two asters are pushed farther and farther apart
- Anaphase is the stage at which the two chromatids of each chromosome are pulled apart at the centromere. All 46 pairs are separated, forming two sets of 46 daughter chromosomes.
- Telophase is the stage at which the two sets of daughter chromosomes are pulled completely apart. Then the mitotic apparatus dissolves and a new nuclear membrane develops around each set of chromosomes.
Pada sel saraf,
adalah lapisan fosfolipid
yang membungkus akson secara konsentrik.
Myelin Membrane Assembly Is Driven by a Phase Transition of Myelin Basic Proteins Into a Cohesive Protein Meshwork
- Shweta Aggarwal,
- Nicolas Snaidero,
- Gesa Pähler,
- Steffen Frey,
- Paula Sánchez,
- Markus Zweckstetter,
- Andreas Janshoff,
- Anja Schneider,
- Marie-Theres Weil,
- Iwan A. T. Schaap,
- Dirk Görlich,
- Mikael Simons
Rapid conduction of nerve impulses requires coating of axons by myelin. To function as an electrical insulator, myelin is generated as a tightly packed, lipid-rich multilayered membrane sheath. Knowledge about the mechanisms that govern myelin membrane biogenesis is required to understand myelin disassembly as it occurs in diseases such as multiple sclerosis. Here, we show that myelin basic protein drives myelin biogenesis using weak forces arising from its inherent capacity to phase separate. The association of myelin basic protein molecules to the inner leaflet of the membrane bilayer induces a phase transition into a cohesive mesh-like protein network. The formation of this protein network shares features with amyloid fibril formation. The process is driven by phenylalanine-mediated hydrophobic and amyloid-like interactions that provide the molecular basis for protein extrusion and myelin membrane zippering. These findings uncover a physicochemical mechanism of how a cytosolic protein regulates the morphology of a complex membrane architecture. These results provide a key mechanism in myelin membrane biogenesis with implications for disabling demyelinating diseases of the central nervous system.
Myelin is a specialized membrane that covers axons and serves as an insulator to enable the fast conduction of the action potentials.
The importance of myelin membrane is highlighted in demyelinating diseases such as multiple sclerosis, which lead to severe neurological disability.
Here, we describe a physicochemical mechanism of how myelin is generated and assembled.
We find that myelin basic protein (MBP) molecules undergo a phase transition into a cohesive meshwork at the membrane interface, which drives structural changes in the membranes.
We provide evidence that the interaction of myelin basic proteins with the inner leaflet of the myelin bilayer results in charge neutralization and triggers self-association of the protein into larger polymers.
Interactions between MBP molecules are mediated by hydrophobic phenylalanine residues and amyloid-like association.
We propose that phase transition of MBP from a cytoplasmic soluble pool into a cohesive functional amyloid-like assembly is one of the key mechanisms in myelin membrane biogenesis
merupakan sel yang membentuk selubung
pada sistem saraf tepi,
sedangkan oligodendrosit merupakan sel yang membentuk selubung yang sama pada sistem saraf pusat.
Selubung mielin merupakan karakteristik dari vertebrata (gnathostome), tetapi juga diangkat oleh evolusi pararel beberapa invertebrata.
Mielin ditemukan oleh Louis-Antoine Ranvier pada tahun 1878.
LT-HSCs derived from diabetic
Cellular Injury and Adaptation
- Tissue injury starts with molecular or structural damage to cells. When faced with injury, cells can either adapt, sustain reversible injury, or die. Cellular adaptation occurs when stressors result in a new but altered state that preserves viability of the cell (eg. hypertrophy, atrophy)
- There are two morphologic patterns of cell death: apoptosis and necrosis
- apoptosis is characterized by chromatin condensation and fragmentation, occurs singly or in small clusters only, and results in the elimination of unwanted cells during embryogenesis and some physiologic and pathologic states
- necrosis is characterized by swelling, denaturation of proteins, breakdown of cellular organelles, and cell rupture
Causes of Cellular Injury
- ischaemia (loss of supply)
- inadequate oxygenation (respiratory failure)
- loss of oxygen-carrying capacity of the blood (anaemia, CO poisoning)
- Physical agents
- thermal insult
- electric shock
- Chemical agents and drugs
- non-therapeutic agents
- Infectious agents
- Immunologic reactions
- Genetic derangements
- Nutritional imbalances
General Mechanisms of Cell Injury
- Oxygen-derived free radicals are produced in many conditions and cause damage to cell structure and function
- Loss of calcium homeostasis, with increased intracellular calcium – this activates phospholipases, proteases, ATPases and endonucleases
- ATP depletion
- Defects in membrane permeability
Ischaemic and Hypoxic Injury
- The key is early loss of oxidative phosphorylation and ATP generation by mitochondria
- Decreased ATP stimulates aerobic glycolysis; glycogen is quickly depleted and lactate and inorganic phosphate produced, dropping intracellular pH
- Manifests histologically as swelling, from:
- loss of Na-K-ATPase, causing sodium to enter the cell, potassium to leave, and an osmotic gain of water
- increased intracellular osmotic load from the accumulation of lactate and inorganic phosphate
- polarized membranes lose their polarity
- All of these are reversible if oxygenation is restored
- The sentinel event for irreversible injury seems to be damage to membranes
- Calcium is probably the most important mediator of biochemical and morphologic alterations leading to cell death
- Reperfusion injury
- mechanism is not well understood, but clinically important particularly to myocardial and cerebral infarction
- definition would be a loss of cells in addition to those irreversibly damaged, by restoration of oxygenation at the end of an ischaemic episode
- bathing compromised cells in high concentrations of calcium when they can’t fully regulate their internal ionic environment?
- local recruitment of inflammatory cells, releasing reactive species?
- incomplete oxygen reduction by damaged mitochondria yielding reactive species?
Free Radical-Induced Injury
- Free radicals are reactive, unstable species that interact with proteins, lipids and carbohydrates. They are created by absorption of radiant energy, oxidative metabolism, or enzymatic conversion of exogenous chemicals.
- Important free radicals are superoxide (from oxygen), hydrogen peroxide, hydroxyls and nitric oxide.
- They damage cells through peroxidation of lipids, cross-linking of proteins by forming disulfide bonds, inactivation of sulfhydryl enzymes, and induction of direct DNA damage
- Free radical termination is by antioxidants (vitamin E, glutathione, ceruloplasmin, transferrin), or enzymes (superoxide dismutase, catalase, glutathione peroxidase)
- Direct injury. Mercury is a good example, binding to sulfhydryl groups of cell membrane proteins, increasing permeability and inhibiting ATPase-dependent transport.
- Indirect injury. Conversion to toxic metabolites (carbon tetrachloride).
Abnormal cell injury in diabetic
Abnormal Cell Injury In Dibetes
Schwann cell injury
in feline diabetic neuropathy
Nerve biopsy samples from two cats with spontaneously occurring diabetes were examined.
The predominant nerve fiber abnormalities observed were restricted to the myelin sheath and Schwann cell.
Reactive, degenerative and proliferative Schwann cell changes were evident but the most striking abnormality encountered was splitting and ballooning of the myelin sheath.
These observations highlight
the significance of Schwann cell injury in the pathogenesis of diabetic neuropathy
THE PATHOGENESIS OF THE LATE COMPLICATIONS OF DIABETES MELLITUS.
Dr Angela Barbour. Discipline of Pathology
University of Adelaide
This material has been reproduced and communicated to you by or on behalf of Adelaide University pursuant to Part
VB of the Copyright Act 1968 (the Act).
COMPLICATIONS OF DIABETES MELLITUS
Large arteries (macroangiopathy): atherosclerosis and related complications
Arterioles: hyaline arteriolosclerosis
Microangiopathy/microvascular: capillary basement membrane thickening
Osteoblasts and Bone Marrow Mesenchymal Stromal Cells Control Hematopoietic Stem Cell Migration and Proliferation in 3D In Vitro Model
- Ana Paula D. N. de Barros,
- Christina M. Takiya,
- Luciana R. Garzoni,
- Mona Lisa Leal-Ferreira,
- Hélio S. Dutra,
- Luciana B. Chiarini,
- Maria Nazareth Meirelles,
- Radovan Borojevic,
- Maria Isabel D. Rossi
Migration, proliferation, and differentiation of hematopoietic stem cells (HSCs) are dependent upon a complex three-dimensional (3D) bone marrow microenvironment. Although osteoblasts control the HSC pool, the subendosteal niche is complex and its cellular composition and the role of each cell population in HSC fate have not been established. In vivo models are complex and involve subtle species-specific differences, while bidimensional cultures do not reflect the 3D tissue organization. The aim of this study was to investigate in vitro the role of human bone marrow–derived mesenchymal stromal cells (BMSC) and active osteoblasts in control of migration, lodgment, and proliferation of HSCs.
A complex mixed multicellular spheroid in vitro model was developed with human BMSC, undifferentiated or induced for one week into osteoblasts. A clear limit between the two stromal cells was established, and deposition of extracellular matrix proteins fibronectin, collagens I and IV, laminin, and osteopontin was similar to the observed in vivo. Noninduced BMSC cultured as spheroid expressed higher levels of mRNA for the chemokine CXCL12, and the growth factors Wnt5a and Kit ligand. Cord blood and bone marrow CD34+ cells moved in and out the spheroids, and some lodged at the interface of the two stromal cells. Myeloid colony-forming cells were maintained after seven days of coculture with mixed spheroids, and the frequency of cycling CD34+ cells was decreased.
Undifferentiated and one-week osteo-induced BMSC self-assembled in a 3D spheroid and formed a microenvironment that is informative for hematopoietic progenitor cells, allowing their lodgment and controlling their proliferation.
Infection -> acute and chronic pyelonephritis
Atherosclerosis related including infarction and renal artery stenosis
Impaired sensation due to neuropathy
Predisposition to infection
Impaired blood supply due to atherosclerosis and microangiopathy impairing healing
Necrobiosis lipoidica diabeticorum (rare)
Predisposition to infection (e.g. pulmonary, urinary tract, skin) related to hyperglycaemia and impaired function of
phagocytes and other inflammatory cells
Liver: non-alcoholic steatosis, steatohepatitis and cirrhosis
Acute metabolic complications
Diabetic ketoacidosis (primarily in type 1)
Non-ketotic hyperosmolar coma (type 2)
Hypoglycaemia from too much insulin or hypoglycaemics
Nephropathy, atherosclerosis, neuropathy, ocular complications
Are late complications
Risk increases in relation to duration of hyperglycaemia
Usually become apparent in 2nd decade of hyperglycaemia, may be present at time of diagnosis of type 2 which often
has a long asymptomatic period
Better blood glucose control reduces risk
Other undefined factors modulate the risk e.g. genetic
Nephropathy, neuropathy, retinopathy are largely related to microangiopathy
Cells include: fibroblasts, myofibroblasts, mast cells, adipocytes, macrophages, undifferentiated mesenchymal cells
Collagen, including reticulin
Ground substance: Glycosaminoglycans bound to proteoglycans
Structural glycoproteins e.g. laminin, fibrillin
Connective tissue proper: loose and dense
Specialised connective tissue e.g. adipose tissue, bone, cartilage
Basement membranes (BM)
Epithelial, endothelial and mesothelial cells sit on a BM
Similar material surrounds Schwann cells and various other connective tissue cells (e.g. adipocytes, smooth muscle
cells) – termed basal lamina
Specialised extracellular matrix
Central electron dense layer (lamina densa) with less distinct electron lucent layers (lamina rara) on either side (all
3 together sometimes termed basal lamina)
Delicate network of predominantly type IV collagen in a matrix of glycoproteins (e.g. laminin) and other
extracellular components (e.g. heparan sulphate proteoglycan) largely produced by the overlying cells
+/- reticular layer: collagen type III originating from underlying connective tissue cells
Often too thin to be seen distinctly on H&E with light microscopy except in areas where it is thicker (e.g. trachea)
but can be seen with special stains on light microscopy
Bonds cells to underlying connective tissue
Provides framework for cell development and regeneration
Freely permeable to small molecules but impedes passage of macromolecules
Intima: endothelium (simple squamous), basement membrane, (+ small amount of connective tissue/elastin in some),
internal elastic lamina (except in smallest arterioles)
Media: variable amounts of smooth muscle and extracellular matrix, predominantly elastin; in some vessels an external
elastic lamina is also present
Adventitia: connective tissue including abundant elastin, vasa vasorum in larger vessels
Large arteries (aorta and it’s main branches): abundant elastic tissue
Medium (distributing arteries) and small (<2mm) arteries: predominantly smooth muscle
Arterioles (diam 100um or less): several layers of smooth muscle cells only
Smooth muscle cells produce the extracellular matrix including elastin
PROPOSED GENERAL MECHANISMS UNDERLYING CHRONIC COMPLICATIONS IN DIABETES:
Complex and not fully understood, different pathways that interact. Genetic factors in the patient also have an important
Formation of advanced glycation end products (AGE) – glucose binds irreversibly to protein amino groups. AGE may
also form on lipids, nucleic acids.
AGE modified extracellular matrix components
Lead to protein cross-linking
Are resistant to proteolytic digestion
Trap other proteins (e.g. plasma proteins)
May promote cell damage
Non-enzymatic glycation of haemoglobin: HbA1c – serves as marker of glycemic control
May alter intracellular signalling, gene expression and oxygen derived free radical formation
Increase in aldose reductase pathway
In cells not requiring insulin for glucose uptake e.g. Schwann cells, retinal pericytes, lens of eye
Metabolism of excess intracellular glucose -> excessive glucose metabolites (e.g. sorbitol) with reduced synthesis of
an important antioxidant -> osmotic cell injury and increased susceptibility to oxidative injury
Production of reactive oxygen species ->
Upregulation of growth factor expression e.g. VEGF
Alteration of proteins and lipoproteins
Increased activation of protein kinase C (PKC) signal transduction pathway
May be related to AGE formation
Activation of signal transduction pathways for extracellular matrix protein production
Overactive renin-angiotensin system
Angiotensin II stimulates production of important growth factors e.g. TGF-beta that plays a role in extracellular
matrix formation in the renal mesangium and VEGF is important in proliferative retinopathy
Important in nephropathy and retinopathy
Understanding pathogenesis helps in the development of potential treatments e.g. use of inhibitors of AGE formation,
antioxidants, angiotensin II inhibitors
The simplified version
Increased amounts of extracellular matrix with altered structure and function due to:
Upregulation (various mechanisms) of production of various growth factors and cytokines -> increased extracellular
AGE modified extracellular matrix proteins -> cross-linking, plasma protein trapping, reduced proteolytic digestion
Cell damage e.g. via aldose reductase pathway and osmotic injury, activation of reactive oxygen species
The microangiopathy (capillary basement membrane thickening), hyaline arteriolar changes and mesangial thickening in
diabetes are caused by the above processes. Hypertension may play a role in the development of hyaline arteriolosclerosis.
Normal renal glomerular structure
Endothelial cells, epithelial cells and basement membrane
Fenestrated with large pores that only prevent blood cells and platelets from passing through
The diaphragm that typically spans fenestrations between endothelial cells in certain other vascular beds is absent
Epithelial cells (podocytes)
Extensive array of processes that interdigitate on outside of capillary with slit like spaces (filtration slits) between
Each filtration slit is spanned by a thin filtration slit diaphragm or membrane
Glomerular capillary basement membrane (BM) of central importance
Made by epithelial and endothelial cells
Composed of collagen type IV, glycoproteins and proteoglycans
No reticular component
Size barrier: molecules larger than about 69,000 daltons unable to cross
Charge barrier: proteoglycan component is anionic (negatively charged), therefore repels negatively charged
Albumin has a molecular weight of 69,000 daltons and is negatively charged
Mesangial cells and extracellular matrix (various collagens and ground substance)
Supports capillary loops
Cells have phagocytic function and clean the basement membrane
May regulate blood flow in capillaries
A clinical syndrome in patients with diabetes mellitus characterised by persistent microalbuminuria, worsening proteinuria,
hypertension and progressive deterioration in renal function. The pathological correlate of diabetic nephropathy is diabetic
glomerulosclerosis characterised by a progressive increase in extracellular matrix in the mesangium and capillary basement
Approximately 25-35% of patients with longstanding diabetes (types 1 and 2) develop diabetic nephropathy and renal failure.
Diabetic retinopathy often also present, especially in type 1 diabetes
Clinical and pathological features and progression
Initial increased intraglomerular pressure with hyperfiltration, potentially at least partly related to vasoconstrictor
effect of angiotensin II on efferent arterioles, associated with enlarged glomeruli, commencing within first few years
Microalbuminuria appears 5–10 years after the onset of diabetes
Onset of overt proteinuria (10-15 years or more after diabetes onset) +/- nephrotic syndrome +/- hypertension,
beginning deterioration in renal function.
Diffuse and nodular diabetic glomerulosclerosis
Diffuse thickening of glomerular capillary BMs (not seen on light microscopy until very thickened)
Diffuse increase in mesangial matrix +/- mild proliferation of mesangial cells
Nodular (Kimmelstiel-Wilson lesion)
Localised nodular areas of increased mesangial matrix with few cells
Less common than diffuse and generally superimposed on diffuse lesion
Insudative glomerular lesions: Eosinophilic nodular accumulations of plasma constituents in capillary loops or in
Hyaline arteriolosclerosis in both afferent and efferent arterioles
Tubular basement membrane thickening
Immunofluorescence: non-specific (not immunologic) trapping of plasma albumin and IgG in tubular and capillary
Most of the changes are not specific for diabetes
Mesangial and glomerular capillary BM thickening related to excessive and altered extracellular matrix:
pathogenesis involves accumulation of AGE products, upregulation of growth factors
Glomerular changes -> narrowing of capillary lumina and glomerular ischaemia, hyaline arteriolosclerosis
contributes to glomerular ischaemia.
Hypertension can contribute to glomerular injury.
Later still: Falling GFR: damaged glomeruli -> impaired renal function. Progressive irreversible glomerulosclerosis,
related tubules atrophy (no blood flow into efferent arterioles and peritubular capillaries) and interstitial tissue undergoes
fibrosis -> further impairment of renal function
End stage renal disease: 5-10 years after development of overt proteinuria (or 10-20 years after onset of
microalbuminuria), however, there is considerable variability between patients. Macroscopically the kidneys may be
slightly enlarged with a granular surface, or small due to co-existent changes related to hypertension or chronic
Pathogenesis of diabetic glomerulosclerosis: complex, at least partly related to microangiopathy (pathogenesis outlined
Various pathways implicated, pathways interact
Hyperglycaemia -> glomerular hyperfiltration and microalbuminuria, altered tubuloglomerular feedback
Vasoconstrictor effect of angiotensin II more potent on efferent arteriole -> increased glomerular capillary pressure
Hypertension may contribute via glomerular hyperfiltration and endothelial and mesangial damage due to
Metabolic factors e.g. AGE mechanism, activation of protein kinase C
Hormonal factors: overactive intrarenal renin angiotensin system (RAS), also contributes to development of
Effects of angiotensin II in kidney
Sodium and water retention by tubules
Can activate other cytokine pathways such as transforming growth factor-beta (TGF-beta) and platelet derived
growth factor (PDGF) systems. TGF-beta-1 stimulates an increase in mesangial matrix deposition and glomerular
basement membrane (GBM) thickening
Impairs nitric oxide function which has vasodilatory and protective role
Can downregulate nephrin, an important protein of the slit diaphragm, leading to proteinuria
Progression slowed by good blood glucose control, strict blood pressure control, administration of ACE inhibitors or
angiotensin receptor blockers (ARBs) and treatment of dyslipidemia.
Proteinuria and nephrotic syndrome
Structural alterations in and loss of negative charge of glomerular capillary BM allow albumin to pass through
Albuminuria is a marker of greatly increased cardiovascular morbidity and mortality for patients with either type 1 or
type 2 diabetes
Hypertension in diabetics
From diabetic nephropathy
From chronic renal failure
Other risk factors e.g. obesity, familial
Renal artery stenosis (less common)
Chronic renal failure (CRF)
Diabetic glomerulosclerosis and hyaline arteriolosclerosis -> chronic glomerular ischaemia -> glomerular
obsolescence/sclerosis and also chronic renal ischaemia with tubular atrophy and interstitial scarring -> poorly
Approx. 30% of patients develop chronic renal failure
Chronic pyelonephritis and hypertension may also cause/contribute to CRF
Remember also that diabetics can get other renal diseases.
Cataracts: from lens swelling and opacity
Glaucoma: formation of fibrovascular membranes on iris related to ischaemia (from microangiopathy) -> blockage of
outflow channels of aqueous humour
Develops in about 75% within 15 years of disease onset
More prevalent among patients with type 1 diabetes than type 2
Often coexists with diabetic nephropathy, but they can also occur independently of each other
Non-proliferative: microvascular changes with pericyte and also ultimately endothelial cell loss, leads to increases in
vascular permeability, vascular weakening and alterations in retinal blood flow, including blockage of capillaries ->
exudates, haemorrhages, microaneurysms, microinfarcts
Proliferative: ischaemia from microvascular changes -> proliferation of small vessels, initially on surface of retina
and later into the vitreous -> haemorrhages, fibrosis and retinal detachment.
Increased VEGF expression, contributed to by hypoxia and oxidative stress is important in pathogenesis of
VEGF is an angiogenic growth factor and increases vascular permeability
Distal symmetric sensory or sensorimotor neuropathy
Symmetric, motor and sensory
?from Schwann cell injury -> demyelination
?from axonal injury
?from microangiopathy impairing blood flow and nutrition of nerve
-> impotence, bowel and bladder dysfunction etc
Severe disabling pain in the distribution of one or more nerve roots
May be accompanied by motor weakness
Focal or multifocal asymmetric neuropathy/mononeuropathy
Affects larger nerves
?from microangiopathy impairing blood flow and nutrition of nerve
Slow build up over years of lipids and fibrous material in the intima of large and medium sized arteries
In diabetics may extend more distally than usual
Pathogenesis in diabetes
Vascular basement membrane and endothelial changes -> increased permeability, trapping of lipids in intima
Anthony S. Fauci, Eugene Braunwald, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, and Joseph
Loscalzo, Eds. Harrison’s online: Harrison’s Principles of Internal Medicine, 17th Edition. The McGraw-Hill Companies.
Ahmed N. Advanced glycation endproducts—role in pathology of diabetic complications. Diabetes Research and Clinical
Practice 2005: 67: 3–21
Caldwell RB, Bartoli M, Ali Behzadian M, El-Remessy AEB, Al-Shabrawey M. Platt DH, Caldwell RW. Vascular endothelial
growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev
2003; 19: 442–455.
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Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy. Med Clin N Am 2004: 88: 1001–1036
Kumar V, Abbas AK, and Fausto N. Robbins and Cotran Pathologic Basis of Disease. 7th edition, 2005. Elsevier Saunders.
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edition, 2005. Lippincott Williams and Wilkins
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Wilkinson-Berka JL. Angiotensin and diabetic retinopathy. The International Journal of Biochemistry and Cell Biology 2006:
Morphology of Reversible Cell Injury and Necrosis
- Two processes cause the basic changes of necrosis: denaturation of proteins, and enzymatic digestion of organelles and cytosol.
- Autolysis indicates digestion by lysosomal enzymes of the dead cells themselves
- The necrotic cell is eosinophilic and glassy, maybe vacuolated. The membranes are fragmented. Nuclear changes include pyknosis (small, dense nucleus), karyolysis (faint, dissolved nucleus) and karyorrhexis (broken into bits)
- Types of necrosis include:
- coagulative (myocardium, kidney, liver – usually ischaemic)
- liquefactive (brain and abscesses – autolysis and heterolysis dominate)
- caseous (tuberculous – soft and cheesy cell debris)
- fatty (adipose – actions of lipases that decompose triglycerides that complex with calcium to form soaps)
- Morphological features include cell shrinkage, chromatin condensation and fragmentation, formation of cytosolic blebs and apoptotic bodies, phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages, and a conspicuous lack of inflammation
- In many instances, it is dependent on gene activation
- Occurs in the following settings:
- programmed cell destruction during embryogenesis
- hormone-dependent involution (eg. endometrium)
- cell depletion in proliferating populations
- pathological atrophy in parenchymal organs after duct obstruction
- cell death by cytotoxic T cells
- cell injury from some viral diseases
- mild traumatic insult
Cellular Adaptation to Injury
- Atrophy = shrinkage in size by the loss of cell substance
- causes include decreased workload, loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, aging
- diminished function but not dead – autophagy, reduced organelles, increased number of autophagic vacuoles; components resisting digestion are deposited as lipofuscin granules, giving a brown appearance
- Hypertrophy = increase in the size of cells (but not their number)
- causes include increased functional demand, hormonal stimulation
- triggered by cell membrane interactions and mechanical factors
- Hyperplasia = increase in the number of cells
- can be physiologic (endometrial proliferation, hyperplasia of the liver after lobectomy) or pathologic (almost always excessive hormonal stimulation)
- when the stimulus is removed, the hyperplasia disappears – this is a crucial difference from neoplasia
- Metaplasia = a reversible change in which one cell type is replaced by another
- examples include Barretts’ oesophagus, the respiratory tract of smokers
- thought to occur from genetic reprogramming
- Lysosomes are involved in digestion of ingested materials through autophagy and heterophagy. It is pronounced in cells undergoing atrophy. Lysosomes with indigestible material may persist within cells or be extruded.
- Hypertrophy of the smooth ER, such as by barbiturates, increasing the surface area available for mixed-function oxidase pathway.
- Mitochondrial alterations, in size, number and function.
- Cytoskeletal abnormalities, which impede transport of organelles and molecules. The basic cell architecture can be disrupted.
- Induction of heat shock proteins. These play a role in normal intracellular protein housekeeping (eg. folding them). They are thought to be induced to refold damaged proteins or to tag them for destruction (ubiquitin).
- Intracellular accumulations – fats (steatosis), cholesterols (atheroma), proteins (Mallory body in alcoholic hepatocytes), glycogen (diabetic renal tubular epithelium), pigments (anthracosis).
- Pathologic calcification, which implies the abnormal deposition of calcium salts in soft tissues. Dystrophic calcification occurs in nonviable tissue, where metastatic calcification is deposition of calcium salts in vital tissues and is associated with hypercalcaemia (hyperparathyroidism, hypervitaminosis D, sarcoidosis, Addison’s disease, hyperthyroidism, bone cancers).
- Hyaline change, intracellularly or extracellularly. This is deposition of proteinaceous material that stains a glassy-pink on H&E.