Flashcards in Lecture 4: Immunological Aspects of the Renal System Deck (73)
Impairment of kidney filtration is activated by the depletion of?
ATP in vascular and tubular cells
Ischemia reperfusion injury results from a generalized or local impairment in?
Oxygen and nutrient delivery to, and waste product removal from cell of the kidney
What occurs to tubular epithelial cells as a result of the imbalance caused by impaired oxygen and nutrient delivery?
Death by apoptosis (clean) and necrosis (dirty death = inflammation)
When endothelium is injured what occurs to the small arterioles in post-ischemic kidney; what amplifies this?
Vasoconstrict more than do vessels from normal kidney; amplified by reduced production of NO and other vasodilatory substances by the damaged endothelial cell
Which inflammatory cytokines amplify the vasoconstriction of the small arterioles; generated how??
TNF-alpha, IL-1B, IL-6, IL-12, IL-15, and IL-18; result of leukocyte-endothelial adhesion and leukocyte activation
The small vessel occlusion and activation of the coagulation system cause what defective functions of the kidney seen in AKI?
- Reduced GFR
- High FENa
- Concentrating defect
What is one of the major causes of ARF?
Ischemic acute kidney injury
Sterile renal inflammation is induced by what, released from who?
Induced by DAMPs; released from dying parenchymal cells
What are the DAMPs released by dying parenchymal cells?
- HMGB1 (nucleolus)
- Uric acid
- HSPs (exosomes)
- Hyaluronans in ECM
- S100 protein in cytoplasm
What happens upon the release of DAMPs?
Immune cells respond to DAMps and induce innate immune responses and subsequent renal inflammation
Which TLR is activated by DAMP's and what occurs?
TLR-4 causing release of NF-kB in turn increasing production of proinflammatory cytokines and adhesion molecules, which elicits a strong inflammatory response
How does apoptosis and necrosis differ in the outcomes seen in AKI?
- Necrosis is the only way DAMPs are released which increased the chance of fibrotic tissue during recovery
- Apoptosis related damage is important for repair
Role of dendritic cells in AKI; cytokines released?
- Regulation of adaptive immune response
- They are APC's, migrate to lymph nodes, and present to T cells; can release Type I IFNs, CXCL2, IL-1B and IL-12.
Role of macrophages in most kidney diseases?
- Regulation of inflammation and fibrosis
- Remain in the tissue of the kidney and secrete ROS, IL-1B, TNF-alpha, IL-6 and chemokines
Macrophages are able to be activated into which two types by what?
M1 - by PAMPs and DAMPs binding to TLR's. IFN-y and other proinflammatory cytokines promote differentiation of M1. M1 then produces cytokine causing more inflammation
M2 - induced by IL-4 and IL-13 produced by TH2 cells. M2 are important in tissue repair and renal fibrosis, both controlled by IL-10 and TGF-B
What is the importance of TGF-B?
Released by M2 and is very important growth factor for fibroblasts (chemoattractant)
What is ratio of M1/M2 seen in AKI?
- M1 will be acting first as neutrophils, NK cells, TH1 and TH17 cells are releasing INF-Y, inflammation will be further exacerbated
- TH2 and Treg cells will promote the differentiation into M2 cells which will predominate and produce anti-inflammatory effects + tissue repair
What is ratio of M1/M2 in CKD?
Due to progressive injury and persistent inflammation, M1's will persist, and this persistent inflammation and fibrotic factors will promote renal fibrosis.
*Products of M1 and M2 are mutually inhibitory, so if M1 is activated, this is inhibiting M2.
Explain how we know complement plays an important role in disease of the kidney; which receptor is the best target?
- Animal models lacking C3, C5, and C6 are protected from renal IRI.
- Deficiency of C3a receptor or C5aR protected mice from IRI, but C5aR were most protected
How do nephrologists determine activation of complement in a given patient?
- Deposition of complement proteins within kidney
- Disturbances of the level of C3 and C4 in the blood
- Detection of C3a and C5a complement activation fragments in the plasma or urine
- Association of mutations and polymorphisms in complement protein with the development of kidney disease
C3a and C5a stimulate chemotaxis of which kind of cell; participates in?
Mast cells increasing by as much as 60x and participate in kidney fibrosis
What starts the adaptive immune response?
DC's activate naive CD4+ T cells in the lymph nodes
Which cytokines and transcriptional factors cause differentiation into TH1, TH2, Treg, and TH17 cells?
TH1: IL-12 and T-bet
TH2: IL-4 and GATA3
Treg: TGF-B and FOXP3
TH17: TGF-B, IL-6 and RORyT
During the adaptive immune response which T cells predominate in the early stages vs later stages?
Early stages: Th17
Later stages: Th1
Resident macrophages are activated by?
Treg cells produce which cytokine and protects against?
Produce IL-10 and are recruited to protect against overwhelming Th1 cell and Th17 cell-mediated immune responses
The clinical outcome of kidney disease mainly depends on?
The balance between pro-inflammatory and anti-inflammatory immune cell
Th17 cells infiltrating early in the immune response secrete what, which stimulates?
Secrete IL-17 which stimulates resident renal cells to produce chemokines and other inflammatory mediators
IL-17 causes the recruitment of ?