1 claude bernard: "it is the fixity of the internal environment that is the condition of free...

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Claude Bernard:

"It is the fixity of the internal environment that is the condition of free and independent life.... All vital mechanisms, however varied they may be, have only one object, that of preserving constant conditions of life in the internal environment".

2Silverthorn Figure 1-2

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  Normal Prolonged, Heavy Exercise

Intake    

  Fluids ingested 2100 ?

  From metabolism 200 200

    Total intake 2300 ?

Output    

  Insensible-skin 350 350

  Insensible-lungs 350 650

  Sweat 100 5000

  Feces 100 100

  Urine 1400 500

    Total output 2300 6600

Balance: matching input and output

Guyton and Hall table 25-1

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Functions of the Kidneys

• Excretion of metabolic wastes• Excretion of foreign substances (e.g., toxins, drugs)• Regulation of body fluid osmolality• Regulation of electrolyte concentrations (e.g., Na+, K+, Ca++)

• Maintenance of water balance and electrolyte balance• Contributes to maintenance of body pH• Regulation of erythrocyte number (how?)• Regulation of blood pressure (how?)• Glucose production

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9Widmaier 14-2

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~1,000,000 nephrons per kidney; 75% cortical and 25% juxtamedullary

(Take a look at the schematic drawing of the capillaries.)

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12From Silverthorn

Urinary excretion rate = filtration rate – reabsorption rate + secretion rate

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So, for each substance:

•To what extent is it filtered in the glomeruli?

•Is it reabsorbed? (if so, where? how>?)

•Is it secreted? (if so, where? How?)

•What factors homeostatically regulate these processes

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Brief overview of transport of molecules across membranes

There are essentially 4 ways the molecules get across membranes:

•Simple diffusion (limited to lipid soluble substances)

•Simple diffusion through holes (i.e., pores) (limited to select ions)

•Carrier-mediated transport (or mediated transport)

•Endocytosis/exocytosis

And, remember, we will be talking not simply about getting molecules across a membrane, but getting molecules across an epithelial cell lining.

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Three factors influence mediated transport:

•Relative affinity of the ligand for the transporter

•How many transporters

•How fast the transporter works

Note: transport maximum; competition

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Mediated transport can be divided into two categories based on whether or not energy is required

•Facilitated diffusion

•Active transport

•Primary

•Secondary

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From the Germann Text

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Simple diffusion Facilitated diffusion Active transport

time time time

[Ci]

[Ci = Co]

Flux

[Co]

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And don’t forget about the movement of water!!

•Osmosis The net diffusion of water down its own concentration gradient

•Movement through water channels (aquaporins)

•Understand osmotic pressure

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Vander

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Getting back to the processes in the nephron: filtration, reabsorption and secretion:

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Consider filtration as the movement of fluid out of fenestrated capillaries into Bowman’s capsule:

24From Silverthorn

Filtration = net filtration pressure X Kf

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26From Widmaier

3 filtration layers:•Capillary endothelial cells (highly fenestrated)•Basal lamina (non-cellular protein matrix)•Podocytes

Haraldsson et al., 2008

27Podocyte wrapped around a glomerular capillary

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FIGURE 1. Renal glomerular filtration system Each human kidney contains ~1,000,000 glomeruli. An afferent arteriole branches into capillaries (glomerular tuft), the walls of which constitute the glomerular filter. The plasma filtrate, the primary urine, is led to the proximal tubules while unfiltrated blood is returned to the blood circulation. The filtration barrier contains fenestrated endothelial cells, the glomerular basement membrane (GBM), and podocytes with their interdigitating foot processes. The slit diaphragm is uniformly wide, porous filter structure containing specific components.

Tryggvason K, Wartiovaara J. How does the kidney filter plasma? Physiology (Bethesda). 2005 Apr;20:96-101.

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• a | Glomerular filtration occurs through the capillary wall into the urinary space, which empties into the proximal tubules. b | The capillary wall contains an innermost fenestrated endothelium, the GBM, and a layer of podocytes with interdigitating foot processes. c | Podocyte foot processes, interconnected by slit diaphragms, form the final barrier for filtration. Proteins that anchor the foot processes to the GBM (   3    1 integrin, ACTN4, ILK and the tetraspanin CD151) as well as those that are associated with the slit diaphragm (nephrin, NEPH1, podocin, Fat1, ACTN4, the adaptor protein NCK, CD2AP, and TRPC6) are crucial for normal function of the filtration barrier. Abbreviations: ACTN4,   -actinin-4; CD2AP, CD2-associated protein; GBM, glomerular basement membrane; ILK, integrin-linked kinase; P, podocin; TRPC6, transient receptor potential cation channel 6.

Patrakka J, Tryggvason K. New insights into the role of podocytes in proteinuria. Nat Rev Nephrol. 2009 Aug;5(8):463-8.

[Note: I don’t expect you to remember these proteins, only that the structure of the slit diaphragm is highly complex.]

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Although we don’t normally think of Kf being a regulated variable, the mesangial cells might act to regulate the size of the podocyte filtration slits

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Let’s consider what contributes to net filtration pressure:

•Pressure inside Bowmans capsule (~ 15 mm Hg) doesn’t change much, unless there is an obstruction in the tubule system

•Capillary pressure can change: regulation by afferent and efferent arterioles

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Silverthorn Figure 19-8 - Overview

Impact of afferent and efferent arteriole changes on GFR

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Glomerular filtration rate:

•125 ml/min; 180 L/day

If we consider the amount of any particular solute in that filtrate, we can come up with the filtered load for that substance:

•In terms of Na, ~3.5g/L so the filtered load is 630G/day

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GFR is stable across a range of blood pressures

- Renal Autoregulation!!

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Two mechanisms contribute to autoregulation:

•Myogenic control (increased pressure causes arterioles to contract)

•Tubuloglomerular feedback (Na delivery to distal tubule is ‘sensed’ in the macula densa, which influences the afferent and efferent arterioles)

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Paracrine signalingEndocrine signaling

Tubuloglomerular feedback

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Consider a substance in blood that is filtered but neither reabsorbed or secreted; it is subsequently excreted:

GFR X Ps = Us X V (where Ps is the plasma concentration of the substance, Us is the urinary concentration of the substance, and V is the urine volume)

so we could determine GFR by: GFR = V X Us / Ps(provided that the substance is filtered but neither reabsorbed or secreted)

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Silverthorn - Figure 19-16

Schematic illustrating the clearance of inulin, and how it relates to GFR