Renal Cellto Cell Communication via Extracellular ATP

1
Renal Cell-to Cell Communication via
Extracellular ATP

• Peter Komiosi, Attila Fintha and P.Darwin Bell
• Reviewed by Laura Crum RN, MS

2
The Normal Kidney and the Renal Glomerular
Filtration System
3
Special Mechanism for Acute Renal Blood Flow
Control Tubuloglomerular Feedback (TGF)

• The composition of fluid in the early distal
  tubule is detected by an epithelial structure of
  the distal tubule (macula densa and
  juxtaglomerular apparatus).

4
Macula densa and the Juxtaglomerular apparatus

• Links fluctuations in NaCl at macula densa with
  control of renal arteriole resistance.
• These feedback mechanisms are dependent on
  juxtaglomerular complex

5
The Mystery of Renal Cell-to-Cell Communication

• Komlosi, Fintha Bell interested in the role of
  ATP and P2 receptors in a signaling process
  between the macula densa and the adjacent
  mesangial cell/afferent arteriole complex

6
Some new terms

• Paracrines vs Autocrines
• Chemical messenger systems help coordinate the
  multiple activies of cells, tissues, organs
• Paracrines- affect function of neighboring cells
  of different type
• Autocrines- affect function of same type cells
  that produced them
• Up regulation
• Stimulation of a hormone causes greater than
  normal hormonal response- i.e. increased number
  of receptors or target tissues become more
  sensitive.

7
Steps in ATP Signaling

• Release of ATP from cell interior
• Extracellular regulation of ATP concentration via
  a rapid enzymatic breakdown
• Binding of ATP to specific receptors
• Currently ATP thought to leave cells thru
  vesicular transport or a channel-mediated release
  but convincing data is lacking

8
Purinergic Receptors

• Adenyl purines (including ATP)
• extracellular nucleotides
• can be release from injured cell or during
  cellular necrosis
• now evidence of regulated release from cell to
  extracellular fluid.
• P1 receptors- activated by adenosine
• P2- bind extracellular ATP
• Found in most mammalian tissue
• P2X- non-selective cation channel thats
  permeable to Ca 2
• G protein-coupled P2Y receptor
• IP3-mediated Ca 2 mobilization to produce cell
  response

9
Release of ATP by macula densa cells

• P2X and P2Y receptors located in apical and
  basolateral membrane of renal epithelial cells
• P2 receptor activation suggested to affect
• renal hemodynamics
• Tubular transport function

10
Arguments for ATP as mediator

• Macula densa cells express very high levels of
  mitochondria and low levels of Na-K-ATPase
  lots of ATP
• Macula densa channel similar to one that conducts
  ATP across mitochondria membrane
• Found PC12 cells that express P2X receptors had
  ATP release with ? luminal NaCl
• ATP release inhibited by furosemide- blocks NaCl

11
Authors conclude

• Paracrine (different cell) signaling that
  involves ATP release across basolateral membrane
  of the macula densa cells.
• Question remains What activates this ATP
  pathway in response to increased luminal
  NaCl????? Maybe basolateral depolarization
  causes cell voltage changes

12
Macula densa signaling

• Exact mechanism controversial
• Both mesangial cells and afferent arteriole
  smooth muscle have P2 receptors
• Juxtaglomerular apparatus have abundant
  nucleotideases to breakdown ATP
• Rapid ATP breakdown- adenosine and P1 receptor
  activation plays role in TGF

13
P1 vs P2 receptor

• ATP-mediated activation of P2X receptors are
  required for TGF-dependent autoregulation of
  afferent arteriole vasoconstriction.
• ATP can easily diffuse into smooth muscle of
  afferent arteriole and bind P2X1 and/or P2Y2
  receptor and produce afferent arteriole
  vasoconstriction.
• P1 receptors
• Adenosine alone can activate without ? in
  mesangial Ca 2
• ATP release across basolateral membrane can cause
  increase mesangial Ca 2 via P2 receptor
  activation

14
Summary Juxtaglomerular vasculature function
may be dependent on breakdown of ATP and
interaction of both P1 and P2 activation

• Because mesangial cells and smooth muscle cells
  of afferent arteriole are interconnected by gap
  junctions reasonable the TGF signals involve P2
  receptor-mediated signaling.

15
Tubuloglomerular Feedback and Control of GFR

• In every nephron GFR modified in response to NaCl
  due to TGF
• Juxtaglomerular function relevance related to
  large amount of fluid and electrolytes that are
  filtered from glomeruli into tubular system.
• TGF-mediated decrease in GFR closes glomerular
  leak to decrease excess fluid and electrolyte
  loss.
• ?TGF efficiency, ?renal perfusion pressure and
  ?GFR

16
Process Incompletely Understood

• 1980s- proposed adenosine- vasoconstrictor
• Angiotensin II- modulating role
• Adenosine must fluctuate for normal TGF
• Adenosine binds to adensoine A1 receptors on
  mesangial cells- renin-afferent arteriole
  vasoconstriction

17
TGF-mediated dynamic and steady-state control of
nephron filtration rate in DM

• Important because diabetes mellitus is leading
  cause of End Stage Renal Disease (ESRD)
• Juxtaglomerular apparatus defect in TGF early in
  DM
• Stable flow predicts ability to stabilize nephron
  filtering
• Glomerular hyperfiltration important in diabetic
  nephropathy
• Diabetic kidney less able to autoregulate

18
Diabetes

• ? glucose? ?cAMP ? ?permeability of epithelial
  cells of renal tubules to water
• Glucose reabsorbed with sodium in proximal tubule
  so excess sodium also reabsorbed
• Less NaCl delivered to macula densa, activating
  TGF-medicated dilation of afferent areterioles
  and increase in renal blood flow and GFR.
• ?NaCl intake
• renal vasodilatation
• ?GFR (hyperfiltration)

19
Salt Paradox in Diabetic Kidney

• A. Early DM
• Enhanced Na- glucose transport
• ? TGF at the macula densa (NaClK)
• Via TGF ?SNGFR
• B. Normal kidney
• C. DM reabsorption in
• proximal tubule sensitive to dietary NaCl

20
Conclusion

• In early diabetes mellitus the TGF is affected
  and can begin the process of damage to the
  kidneys.
• Its important to determine ways to prevent the
  early glomeruli alterations that lead to nephron
  dysfunction and damage.
• Altering salt intake may help.

21
References

• Thomson, S.C., Vallon, V. and Blantz, R.C.
  (2004). Kidney Function in Early Diabetes The
  Tubular Hypothesis of Glomerular Filtration.
  American Journal of Physiology Renal
  Physiology. http//ajprenal.physiology.org/cgi/co
  ntent/full/286/1/F8
• Guyton and Hall (2006). Textbook of Medical
  Physiology, 11th Ed.