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Lecture 11

HSS 3505 Lecture Notes - Lecture 11: Polycystin 2, Colorectal Cancer, Basal-Cell Carcinoma

Health Sciences
Course Code
HSS 3505
Karen Phillips

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Patho Renal Physiology (11)
How important is the kidney?
- Fluid regulation
o Blood pressure
o Cardiovascular output
o Imbalances
Congestive heart failure
o Acid/base balance
o Waste elimination
o Drug excretion pharmacology
Kidney Structure
- inner medulla and outer cortex
- nephrons: functional units located in renal cortex:
o renal corpuscle: filtering unit with glomerulus and glomerular capsule
o renal tubule: proximal convulated tubule, loop of henle, distal convulated
Renal Physiology
- urine production promotes homeostasis by regulating volume and composition of
- three organic waste products:
o urea: most abundant waste
o creatinine: produced in skeletal muscle tissue
o uric acid: formed by recycling nitrogenous base from RNA molecules
Urine Formation
- kidneys return filtered fluid to internal environment through tubular reabsorption
- waste products are excreted in urine
- tubular secretion removes hydrogen ions and toxins faster than through filtration
Renal Disease
o horseshoe kidney
o polycystic kidney disease
wilms tumor
o Diabetic nephropathy
o Glomerulonephritis
o Kidney stones
o Kidney tumors
Wilms tumor
Renal cell carcinoma
o Pyelonephritis
o Renal failure
Acute renal failure
Chronic renal failure
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Congenital: Horseshoe Kidney
- affecting about 1 in 400 people
- in which a person’s two kidneys fuse together to form a horshoe-shape during
development in the womb
- complications-kidney stones, urinary tract infections
- often asymptomatic and discovered at autopsy
Congenital: Polycystic Kidney Disease
- progressive, genetic disorder
- characterized by the prescence of multiple cysts in both kidneys
- can also damage the liver, pancreas, rarely heart and brain
- autosomal dominant polycystic kidney disease (ADPKD) is generally a late-
onset disorder characterized by progressive cyst development and bilaterally
enlarged kidneys with multiple cysts. End stage renal failure (50%)
- autosomal recessive polycystic kidney disease (ARPKD) is much rarer than
ADPKD and is often fatal in utero or during the first month of life
Autosomal dominant polycystic kidney disease (ADPKD)
- mutations in PKD1 (85% cases) polycystin-1 (PC1) protein
- mutations in PKD2 (15%) polycystin -2 (PC2) protein
- transmembrane glycoproteins involved in Ca2+ signalling
- polycystins co-localize with fibrocystin at the primary cilia of renal epithelial
- decreased Ca2 levels/signaling pathways subsequent accumulation of cAMP
- dysregulation of CFTR cl-channel involved in the formation of cysts
- increased cell proliferation and apoptosis
Autosomal recessive polycystic kidney disease (ARPKD)
- Approximately 30% of affected infants die in the neonatal period or within the
first year of life
- More than 50% of affected children progress to end-stage renal disease, usually in
the first decade of life
- Mutations in PKHD1
o Encodes fibrocystin (FC)
Mechanism Cyst Formation
- Disruption of the polycystin (PC) /fibrocystin (FC) pathway decreased Ca2+
o stimulate adenylate cyclase (AC)
o inhibit phosphodiesterase (PDE) increased cAMP levels/PKA pathway
- activation of protein kinase A (PKA) stimulates cell proliferation by MAPK
- in polycystic kidney disease, cAMP-PKA signaling increases the permeability and
expression of CFTR Cl channels
o Cl effux from cell
o increases Na+ efflux from cell
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- water moves from cell into the lumen of the cyst
Diabetic Nephropathy
- progressive kidney disease caused by angiopathy of capillaries in the kidney
- characterized by nephrotic syndrome (protein in urine) and nodular
glomerulosclerosis (hardening of glomerulus)
- due to longstanding diabetes mellitus, and is a prime cause for dialysis in many
western countries
- inflammation of renal glomeruli caused by antigen-antibody reaction within
glomerular capillaries
- interaction of antigen-antibody activates complement and liberates mediators that
attract neutrophils
- actual glomerular injury is caused by destructive lysosomal enzymes that are
released from the leukocytes that have accumulated within the glomeruli
Kidney Stones
- also called renal calculi, are solid concretions (crystan aggregations) of dissolved
minerals in urine
- calculi typically form inside the kidneys or bladder
- nephrolithiasis: presence of calculi in kidneys
- urolithiasis: presence of calculi in the urinary tract
- obstruction with dilation or stretching of the upper ureter and renal pelvis
- spasm of muscle, severe episodic pain, most commonly felt in the flank, lower
abdomen and groin upon attempts to pass stone (urination)
- hematuria (bloody urine) is commonly present due to damage to the lining of the
urinary tract
- recurrence rates are estimated at about 10% a year, men are affected
approximately 4 times more often than women
- causes related to metabolic syndromes
Kidney Tumors: Wilms Tumor
- wilm’s tumor or nephroblastoma is a tumor of the kidneys that typically occurs in
children, rarely in adults
- treatment-removal of tumor/kidney
- Genetics:
- Mutations in WT1
o Wilms tumor protein
o Transcription factor
o Interactions with p53
Epigenetic/genomic alterations
Chromosome 11, 17, 19, chromosome x
Kidney Tumor Renal Cell Carcinoma
- renal cell carcinoma (RCC) is the most common form of kidney cancer
- collection of different types of tumors, each derived from various parts of the
nephron (epithelium or renal tubules)
o clear cell renal carcinoma (CCRCC)
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