Alpha2A-adrenoceptors in renal inflammation and fibrosis

• Applicant: Professor Dr. Johannes Stegbauer
• Subject Area: Nephrology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 315973252

The prevalence of chronic kidney disease (CKD) is increasing. Independent from the underlying disease CKD patients have a high cardiovascular morbidity and mortality. CKD is characterized by a progressive development of tubular-interstitial fibrosis due to chronic inflammatory processes and maladaptive organ remodeling. Renal replacement therapy becomes often necessary. Low dose immunosuppressive therapy seems to protect kidney function by attenuating inflammation. However, the exact mechanisms triggering inflammation mediated progression of CKD are still not fully understood. In CKD, sympathetic nerve activity is significantly increased, which contributes to the progression of CKD and cardiovascular morbidity and mortality. In the last funding period, we could clearly demonstrate that prejunctional alpha2A-adrenoceptors (α2A-AR) mediate inhibition of sympathetic norepinephrine release in the kidney to prevent accelerated hypertensive kidney damage. When inhibitory α2A-AR are deleted, more norepinephrine is released in angiotensin II-dependent hypertension causing pronounced renal vasoconstriction, vascular hypertrophy as well as sodium- and water reabsorption. This dysregulation leads to glomerular and tubulointerstitial injury and fibrosis. Beside these effects, α2A-AR are also involved in immune cell responses causing organ dysfunction. Thus, there are two potential mechanisms by which α2A-AR may modulate inflammation and fibrosis in CKD. First, increased norepinephrine release from sympathetic nerves in lymphatic organs can modulate immune cell phenotype and function. And second, α2A-AR expressed on immune cells can modulate their phenotype and function, and thereby contribute to the development of fibrosis in different animal models. Preliminary results show that norepinephrine increased the expression of proinflammatory M1 (LPS+IFNγ) markers on macrophages, such as iNOS, IL-6 and TNF-α. Furthermore, we also demonstrate that transplantation of bone marrow from α2A-AR-KO mice into WT mice significantly reduced the development of renal inflammation and fibrosis in kidneys after unilateral ureter obstruction suggesting an important role of α2A-AR on immune cells. However, the exact underlying mechanism and the cell-type responsible for these effects remains unclear. Therefore, the overall goals of this project are to investigate (1) the contribution of an increased sympathetic norepinephrine release on immune cell phenotype and function and to identify (2) the role of α2A-AR expressed on macrophages and T cells in the development of inflammation and renal fibrosis. To master this important task, we already generated cell-type specific α2A-AR deficient mice where we deleted α2A-AR either from prejunctional adrenergic cell, from macrophages or T cells.

• DFG Programme: Research Grants