Pathogenic role of mast cells in tubulointerstitial fibrosis development in chronic kidney disease

• Grant number: 14/06991-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2014
• End date: January 31, 2017
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Lislaine Andrade Wensing
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 12/02270-2 - New cellular, molecular and immunological mechanisms involved in acute and chronic renal injury: the search for new therapeutical approaches, AP.TEM
• Associated scholarship(s): 15/11868-7 - Mast cell tryptases and experimental chronic kidney disease, BE.EP.PD

Abstract

Chronic kidney disease (CKD) is the result of progressive loss of functional nephrons. Regardless of the initial insult, CKD manifests itself as glomerulosclerosis, vascular sclerosis and tubulointerstitial fibrosis. It is believed that this last change is the best predictor of decline in renal function and poor prognosis. The tubulointerstitial fibrosis is characterized by accumulation of fibroblasts, interstitial deposition of extracellular matrix (ECM ), epithelial-mesenchymal transition of tubular cells and loss of tubular architecture and microvasculature. These phenomena are usually preceded by infiltration of inflammatory cells. Although several studies have addressed the role of T lymphocytes and macrophages in the pathogenesis of tubulointerstitial fibrosis, a possible involvement of mast cells (MCs) in this process has been forgotten or even ignored. MCs are normally present in low numbers in the kidneys, however it is observed accumulation of these cells in the interstitial and perivascular areas of kidneys from patients with CKD, regardless of disease etiology. Besides, MCs increased numbers are positively correlated with the degree of tubulointerstitial fibrosis and declining renal function. Recently, the role of MCs as effectors cell in tubulointerstitial fibrosis has been consolidated from the results obtained with animals treated with MCs stabilizers or deficient in these cells. It was demonstrated in these conditions a lower degree of tubulointerstitial fibrosis and impairment of renal function after experimental models of acute and chronic kidney injury. Interestingly, it was also seen that the accumulation of mast cells preceded the infiltration of T lymphocytes and macrophages and that the recruitment of these cells was impaired in mast cell deficient mice. MCs are derived from multipotent progenitors in the bone marrow and migrate into vascularized tissues where they complete their maturation, acquiring tissue specific phenotype. Although traditionally known for their role in the allergic response, are currently considered important mediators and modulators of innate and adaptive immune response, chronic inflammation and peripheral tolerance, and act in tissue remodeling and fibrosis in different organs. Once activated, MCs secrete numerous vasoactive pro- inflammatory and pro-fibrotic mediators. These include pre-formed molecules, such as histamine, TNF, TGF- ²1, tryptase and chymase, which are stored in secretory granules. Leukotrienes and prostaglandins are synthesized during its activation. In addition, several cytokines and VEGF are synthesized de novo and secreted several hours after the stimulation. It is known that MCs produce renin and chymase is the main responsable for angiotensin II (Ang II) generation independently of angiotensin converting enzyme (ACE). It has been suggested that increased intrarenal Ang II production by MCs would be a potential mechanism by which these cells induce renal fibrosis. It was also shown that other molecules secreted by MCs regulate proliferation and ECM production in different cell types such as fibroblasts and epithelial cells in fibrotic diseases. Our hypothesis is that by the secretion of pro-inflammatory and pro-fibrotic factors, MCs are involved in the different processes leading to tubulointerstitial fibrosis, and inflammation, recruitment and activation of fibroblasts and epithelial-mesenchymal transition of tubular cells.