Renal

Question 1

Explain the mechanisms underlying hypertension

Question 2

explain how reduced nitric oxide levels can induce hypertension

Question 3

explain the

Answer 3

novel treatments for hypertension based on the L-arginine-nitric pathway

Question 4

To define heart failure with preserved ejection fraction and heart failure with reduced ejection fraction

Question 5

explain the mechanisms which link heart failure with renal failure

Answer 5

overactivation of the sympathetic nerves and overactivation of the renin angiotensin system
increase oxidative stress and reduce nitric oxide bioavailability contributing to kidney fibrosis and inflammation which in turn lead to a decline in glomerular filtration rate (GFR) in heart failure

Question 6

explain the pathogenic role of nitric oxide deficiency in development of heart failure related renal disease

Question 7

Explain recent research in the field of cardiorenal disease

Question 8

Explain the role of oxidative stress in cardiorenal syndrome

Question 9

Explain how we can use antioxidants to target oxidative stress in cardiorenal
syndrome

Question 10

Explain the effects of serelaxin (a drug from Novartis which can reduce oxidative stress) on cardiorenal syndrome

Question 11

Explain the role of the renin angiotensin system in cardiorenal syndrome

Question 12

What are the mechanisms of obesity-induced hypertension

Answer 12

Visceral obesity leads to an increase in Leptin, RAAS activation, renal compression, and metabolic disorders, which then leads to SNS activation, and an increase in renal sodium reabsorption, which leads to an increase in blood pressure causing hypertension followed by chronic kidney disease. The Glomerular also undergoes hyperfiltration which contributes to the development of chronic kidney disease

Question 13

What are a few functions of Nitric Oxide (NO)

Answer 13

• NO is a vasodilator
• NO plays a central role in regulating extracellular fluid homeostasis
• NO plays a key role in the regulation of renal blood flow and blood pressure
• Reduction in NO bioavailability can lead to hypertension and kidney disease

Question 14

What are the 3 ways to increase nitric oxide bioavailability in the cardiovascular system

Answer 14

1. First compounds such as L-arginine, L-citrulline, and arginase inhibitors increase substrates and cofactors necessary for NO synthase activity.
2. blocking endogenous inhibitory pathways will increase NO bioavailability. ACE inhibitors, Ang 2, receptor 1 blockers and NADPH oxidase inhibitors will reduce the formation of superoxide thereby limiting NO scavenging and peroxynitrite generation increasing NO bioavailability
3. statins, polyphenols, nebivolol, and corticosteroids are able to increase endothelial NOS activity mainly through phosphorylation. Inhibitors of endogenous NOS inhibitors also increase endothelial NOS. Finally, NO can be directly inhaled or can be derived from organic nitrates.

Question 15

How does the use of organic nitrates increase nitric oxide

Answer 15

Upon nitrate bioactivation, NO stimulates soluble guanylyl cyclase, increases cyclic 3 and 5 cGMP that activates cGMP-dependent protein kinase, and subsequently decreases intracellular calcium levels. The decreased calcium levels reduce the contractility of myosin/actin filaments via inhibition of the myosin light chain phosphorylation and therefore cause vasorelaxation

Question 16

Explain what occurs when NO gas is inhaled but why it is not a long-term solution

Answer 16

inhaled NO gas clearly vasodilates the pulmonary circulation and improves ventilation–perfusion matching and oxygenation in patients with acute lung injury, but this response is transient, only lasting a few days.

Question 17

L-arginine as a hypertension cure

Answer 17

Augmented endothelial L-arginine transport can ameliorate obesity-induced hypertension

Anti-hypertensive effects of endothelial L-arginine transport are mediated by preserving NO bioavailability. This inturn buffers the activity of the sympathetic nervous system and renal renin-angiotensin system (RAS).

Question 18

What did the research find about Endothelial CAT1 overexpression

Answer 18

Endothelial CAT1 overexpression can ameliorate obesity-induced
hypertension by preserving NO levels and thereby buffering the actions of the sympathetic nervous system.
Thus, L-Arg transport is likely to be a potential new treatment target in
obesity-dependent hypertension.

Question 19

What is the difference between heart failure with Preserved ejection fraction vs Reduced ejection fraction

Answer 19

• HF Preserved ejection fraction is Diastolic heart failure, where the walls are thickened and stiff resulting in the heart struggling to fill
• HF Reduced ejection fraction is Systolic heart failure, where the walls are thin and dilated resulting in the heart struggling to pump

Question 20

What are the systemic factors that contribute to cardiorenal syndrome

Answer 20

• Diabetes
• hypertension
• obesity
  -metabolic syndrome
• amyloidosis

Question 21

mechanisms underlying the relationship between heart failure (HF) and renal dysfunction

Answer 21

• HF causes the sympathetic nervous system to activate the RAAS causing a few of the following, a decrease in cardiac output resulting in a decrease in renal blood flow / GFR resulting in renal dysfunction. HF also causes activation of RAAS causing an increase in oxidative stress and a decrease in nitric oxide, leading to inflammation and fibrosis resulting in renal dysfunction

Question 22

what are mechanisms underlying the relationship between heart failure (HF) and renal dysfunction

Answer 22

overactivation of the sympathetic nerves and overactivation of the renin angiotensin system
increase oxidative stress and reduce nitric oxide bioavailability contributing to kidney fibrosis and inflammation which in turn lead to a decline in glomerular filtration rate (GFR) in heart failure

Question 23

How does reduced nitric oxide impact kidney function?

Answer 23

• reduce renal perfusion
• Impair sodium and water reabsorption
• Reduce glomerular filtration rate
• Impair tubuloglomerular feedback mechanism
• Impair myogenic response
• Enhance renal vasoconstrictor responses to renal sympathetic nerve activity, thereby leading to renal ischemia
• Augment the vasoconstrictor activity of the renin angiotensin aldosterone system (RAAS)

Question 24

What are the actions of ANG II

Answer 24

Actions of ANG II:
* potent vasoconstrictor – nitric oxide
counteracts this effect
* activates sodium reabsorption
* stimulates aldosterone production
* Stimulates ADH release

Question 25

What is the first line treatment in kidney disease

Answer 25

ACE inhibitors: First line treatment in kidney disease. ACE
inhibitors can increase nitric oxide and reduce oxidative stress

Question 26

How does reduced nitric oxide bioavailability contributes to cardiorenal syndrome

Answer 26

1. Increases the expression of proinflammatory
   markers (IL-6)
2. Reduces the expression of antiinflammatory
   markers (IL10)
3. Increases fibrosis (PAI-1)
4. Increases oxidative stress
5. Leads to cardiac dysfunction
6. Leads to renal ischemia and
   dysfunction

Restoring the bioavailability of NO via genetic overexpression of CAT-1 can prevent inflammation, development of
renal fibrosis, and therefore preserve renal function in the setting of CRS

Question 27

How does RAAS activation contribute to fibrosis and cardiorenal syndrome?

Answer 27

• Renin angiotensin aldosterone system (RAAS) activation increases oxidative stress
• Oxidative stress reduces nitric oxide
• Reduced nitric oxide levels can activate pro-fibrotic pathways, this includes increasing the expressing of plasminogen activator inhibitor-1 (PAI-1). PAI-1 contributes to fibrosis in the heart and the kidney.
• Fibrosis leads to impaired function of the heart and the kidney which contributes to cardiorenal syndrome

Question 28

How can N-acetylcysteine (NAC) reduce oxidative stress

Answer 28

Administration of NAC increases glutathione synthesis, restores NO
bioavailability and therefore reduces oxidative stress which attenuates fibrosis and renal
dysfunction in the setting of CRS

Question 29

How does the administration of N-acetylcysteine (NAC) exerts reno protective effects in heart failure

Answer 29

• Reducing the expression of pro fibrotic marker plasminogen activator inhibitor-1 (PAI-1)
• Increasing the expression of the anti-inflammatory marker Interleukin 10 (IL-10)
• Reducing renal collagen type 1. (note collagen type 1 contributes to fibrosis)
• Reducing glomerular and tubulointerstitial fibrosis which in turn increases glomerular filtration rate

Question 30

How does Serelaxin reduce inflammation and fibrosis

Answer 30

The administration of serelaxin tended to restore NO bioavailability in MST-1 mice. This was associated with a reduction in inflammation and renal fibrosis. Overall, targeting NO-oxidative stress imbalance in CRS appears to be beneficial

This was done by
* Reducing the expression of IL-6
* Increasing the expression of the anti-inflammatory marker IL-10

Question 32

What happens to L-arginine-nitric oxide pathway activity in obesity

Answer 32

L-arginine-nitric oxide pathway activity is reduced in obesity

Question 33

What can reduce kidney fibrosis in experimental heart failure

Answer 33

Augmented cationic amino acid transporter-1 (CAT-1) expression in endothelial cells

Question 34

What mechanism contributes to development of kidney disease in obese individuals

Answer 34

Chronic over-activation of the renin angiotensin aldosterone system (RAAS) contributes to the development of kidney disease in obese individuals

Question 35

What is a substrate for nitric oxide production

Answer 35

L-arginine