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BY2202 The Kidney and Urinary Tract Origin, Form and Function 1 Dr. Neil Docherty Relevant Learning Outcomes From BY2202 • Interpret cell-cell communication in the nervous and endocrine systems • Outline the evolution and development of the renal and digestive systems • Describe the fundamental structure and function of the human cardiovascular, respiratory, renal and digestive systems N.B. • We will be focusing on development of the human kidney and its role as a key element of integrative physiology • Drawing attention to its role in a couple of homeostatic mechanisms -volume regulation -Red blood cell production (erythropoesis) Todays Objec=ves • To summarise the sequen/al development of the mature kidney • To highlight the role of reciprocal induc=ve events (epithelial-‐mesenchymal interac/ons) in nephrogenesis • To detail the organisa/on of the nephron as the func/onal unit of the kidney • To link func/onal phenomena in the nephron (filtra=on, reabsorp=on, secre=on) to func/onal endpoints (excre=on, volume and pH regula=on) Prologue What the Urinary System Contributes to The Body Through the production of urine and hormones 1) WASTE EXCRETION 2) EXTRACELLULAR FLUID SALT/WATER BALANCE 3) REGULATION OF pH in EXTRACELLULAR FLUID 4)REGULATION OF RED BLOOD CELL PRODUCTION (ERYTHROPOESIS) Perspective Check The job of the kidney should not be listed as “making urine”, rather the production of urine is a mechanism through which the kidney delivers on major homeostatic functions (1-3 above). Func=onal Anatomy of The Mature Kidney Functional unit is The Nephron • Cortex • Medulla – Pyramids • Sinus – Minor calices – Major calices – Renal pelvis “coronal” view of kidney • Ureter Kidney Development (Nephrogenesis) ECTODERM Week 3 of human development MESODERM ENDODERM • Muscle • Cartilage • Bone • Dermis • Vascular system • Urogenital system • Adrenal Cortex *See notes from lectures 3,4 and 5 of BY1101 with Professor Paula Murphy Key Concepts; Cleavage. Gastrulation, Organogenesis, Induction) Nephrogenesis Originates in the Intermediate Mesoderm 17d 20d 19d 21d Looking in at a cross section of the embryo we see PARAAXIAL-INTERMEDIATE AND LATERAL PLATE FORMED Nephrogenesis (Chronology along Longitudinal Axis) • Three systems develop – Pronephros (week 4) • Degenerates • Leaves no remnant – Mesonephros (weeks 4-‐8) • Degenerates • Leaves its duct – Metanephros (week 5) • Persists • Becomes the mature kidney Emergence of The Collec=ng System (Branching of The Ureteric Bud) • Ureteric bud forms the collec/ng system • Ureter • Renal pelvis • Major calices • Minor calices • Collec/ng tubules (1 -‐ 3,000,000) Forma=on of the Filtra=on and Renal Tubular Components Establishment of excretory units (nephron) • Sieve from blood (glomerulus)-vascular derived • Excretory epithelial tube (tubule)-derived from connective tissue around branches of ureteric buds • Linkage to collecting system (ureteric bud derived component) Molecular Control From Last slide Excretory epithelial tube (tubule)-derived from connective tissue around terrminal buds • The ureteric bud enters the metanephros • It induces the metanephros to form tubules • The metanephros reciprocally induces the ureteric bud to con/nue to proliferate and form the collec/ng system Reciprocal epithelial-‐mesenchymal interac2on Driven by growth factors and transcrip2on factors Molecular Control-1 Step 1 • The metanephros expresses WT1 – Required for competence to respond to induc/on – Leads to produc/on of • GDNF • HGF Molecular Control-2 Meanwhile • The ureteric bud forms (tyrosine kinase) receptors – RET • for GDNF – MET • for HGF Molecular Control-3 Consequently • A signaling pathway is now established • GDNF and HGF • Promote growth and branching of the ureteric bud Molecular Control-4 Reciprocally • The ureteric bud produces – FGF2 – BMP7 • Metanephric growth • Maintain WT1 produc/on Molecular Control-5 Furthermore • The ureteric bud produces • WNT9B • WNT6 • The metanephros responds by producing • PAX2 • WNT4 – PAX2 • Condensa/on of the mesenchyme – WNT4 • Epithelialisa/on of the condensed mesenchyme Outcome • Collec/ng system develops from ureteric bud • Nephrons (excretory units) develop from metanephros • Metanephric cells have largely changed from a mesenchymal to an epithelial configura/on Renal agenesis • Unilateral (~1 / 750) – Increased risk of hypertension? • Bilateral (~1 / 10,000) – Including agenesis of the ureters – Muta/ons affec/ng GDNF – Fatal within hours of birth • Oligohydramnios and Pocer Sequence • Lung hypoplasia • Other severe problems in 85% Summary Origin, Regions and Maturation DEVELOPMENT WEEK 5 “sagittal” view of embryo THE METANEPHRIC AND MATURE KIDNEY “coronal” view of kidney • • • • Cortex Medulla – Pyramids Sinus – Minor calices – Major calices – Renal pelvis Ureter 1x106 nephrons Establishment of excretory units (nephron) • Sieve from blood (glomerulus) • Excretory epithelial tube (tubule) The Nephron-Functional Unit of Kidney (A Closer Look at Microanatomy and Cell Types) Review the detail below after second lecture Cells of the Vascular Component (Endothelium, vascular smooth muscle cells stretch sensory afferents neurones, sympathetic fibres pericytes) Cell of the Tubular Component (Epithelium, Osmosensory Cells) Cells of Stromal Component Mesangial cells Functionality Associated With Nephron (8 KEYWORDS) The phenomena of FILTRATION, REABSORPTION and SECRETION As tuned by INTRINSIC and EXTRINSIC control mechanisms Leads to delivery on the key functions of • EXCRETION • VOLUME REGULATION • pH REGULATION N.B. Two types of nephrons Cortical (more excretory) Juxtamedullary (more involved in volume regulation) Today’s Learning Outcomes From today’s lecture, you should be able to; 1) Summarise the steps involved in the sequen/al development of the mature kidney 2) Highlight the role of reciprocal induc/ve events (epithelial-‐mesenchymal interac/ons) in nephrogenesis 3) Detail the organisa/on of the nephron as the func/onal unit of the kidney 4) Explain the significance of the terms filtra/on, reabsorp/on, and secre/on in terms of nephron func/on