Mast cells in kidney disease

Kidneys are essentially large filters. Blood is passed through endothelial cells in blood vessels, then filtered through a membrane made up of structural molecules. The filtrate then moves into kidney tubules where it becomes urine and is pushed out towards the bladder. During this process, the kidneys carefully remove substances from urine and put other substances into it in order to regulate available water, electrolyte concentration and blood pressure.

Chronic kidney disease can be caused by a variety of insults, including diabetes, high blood pressure, genetic conditions, chemical exposure, damage from shock, autoimmune disease and infections. Regardless of the underlying reason, once the kidney is injured, it can become sclerosed and fibrosed if not healed correctly. This can ultimately cause kidney failure. The kidney is able to function well even when a significant portion is damaged. For this reason, kidney disease is often not identified until 60-70% of functional kidney cells have been damaged beyond repair.

Mast cells have very complex and nuanced roles in renal disease. In healthy kidneys, mast cells are rare. In the presence of kidney disease, mast cells form a significant infiltrate, with counts increasing by as much as 60 times compared to healthy controls. IgA nephropathy, lupus nephritis, diabetic nephropathy and renal tubulointerstitial fibrosis are all conditions in which mast cell count has been correlated with degree of kidney fibrosis. Mast cell growth factors such as stem cell factor (SCF) are elevated in affected kidney tissue. However, mast cell count has not been shown to be related to severity of disease in any models thus far.

Mast cells are not the only allergic actor involved in kidney disease. Atopy (having allergic conditions like atopic dermatitis or allergic asthma) has been linked to idiopathic nephrotic syndromes in which patients experience kidney damage for unknown reasons. These patients often have multiple severe allergies and have serum IgE levels higher than found in other kidney diseases. Furthermore, IgE levels stay high in patients that relapse. Allergy immunotherapy and trigger avoidance has been trialed in these patients with mixed results. Many researchers believe that in these patients, the nephritis and allergies are both manifestations of one underlying condition.

IgE levels are also increased in nephritis caused by lupus (SLE). Basophils, different cells involved in allergies, make antibodies to IgE, causing an inflammatory response and worsening this type of nephritis.

Kidney damage can be caused by heavy metals and chemicals, including some types of chemotherapy. Tryptase is significantly elevated in patients with this kind of damage. In these patients, neutrophils and CD4+ T cells quickly infiltrate affected kidney tissue. In animal models where they are mast cell deficient, this infiltration by neutrophils and T cells is less efficient. This means that mast cells are involved in drawing these cells to the kidney. Treatment of the tissue with cromolyn also decreases the level of infiltration.

Mast cells are known to participate in fibrosis both in the kidney and elsewhere. Mast cells release fibrosis driving molecules like type VIII collagen in diabetic nephropathy; fibroblast growth factor in IgA nephropathy; and release tryptase, chymase and carboxypeptidase A, which participate in remodeling and fibrosis, in a number of conditions. Tryptase can also cause proliferation of fibroblasts.

Fibrosis develops largely due to the activity of TGFb and angiotensin II, which can be regulated by mast cells. Chymase can generate angiotensin II, which increases blood pressure and can further aggravate kidney conditions. In biopsies for which chymase staining is positive, fibrosis is significant. Renin, a molecule that regulates angiotensin II, is also released by mast cells.

In spite of these data, there is also significant evidence that in some instances, mast cells are protective against kidney disease. In some research models where mast cells are deficient or absent, kidney damage progresses more quickly. Levels of IL-4 and TGFb1, which can drive kidney damage, are higher in mast cell deficient models. Heparin, a mast cell mediator, is known to interfere with production of TGFb1.

In some cases, mast cells even protect against kidney fibrosis. Mast cells have been found to degrade fibronectin, which other cells need to filtrate the kidney. Mast cells can also prevent deposition of fibrin and type I collagen, which contributes to fibrosis.

References:

Madjene, LC., et al. Mast cells in renal inflammation and fibrosis: Lessons learnt from animal studies. Molecular Immunology 63 (2015) 86-93.

Blank, U., et al. Mast cells and inflammatory kidney disease. Immunol Rev 2007, 217: 79-95.

Summers, SA., et al. Mast cell activation and degranulation promotes renal fibrosis in experimental unilateral ureteric obstruction. Kidney Int 2012.

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