Abstract Number: PB1776
Meeting: ISTH 2020 Congress
Background: Diabetic nephropathy (dNP) is the leading cause of end stage renal disease worldwide. Diabetes is associated with elevated levels of FXII and other contact coagulation pathway proteins. FXII signaling is linked to the pathogenesis of several inflammatory conditions including pulmonary fibrosis, atherosclerosis and cutaneous wounds. Whether FXII plays a role in dNP is currently not known.
Aims: To identify the role of coagulation FXII in dNP and to elucidate the involved signaling pathways.
Methods: Wild type (Wt) and FXII knockout mice (FXII-/-) were used in this study. Persistent type-1 diabetes was induced using streptozotocin and was maintained for 24 weeks, followed by ex-vivo and in vitro studies to obtain mechanistic insights. Additionally, human samples were studied to determine translational relevance.
Results: In diabetic FXII-/- mice albuminuria, tubulointerstitial fibrosis and glomerular damage were ameliorated compared to diabetic Wt mice. Increased tubular expression of FXII was observed in human and mice diabetic kidney sections. Activated FXII was detected in urine samples from human and diabetic mice. Markers of inflammasome activation (cleaved Casp-1 and IL-1β, NLRP3 expression) were reduced in kidney lysates of FXII-/- mice as compared to Wt mice. Renal expression of urokinase‐type plasminogen activator receptor (uPAR), which is strongly induced in diabetic WT mice, was normalized in diabetic FXII-/- mice. Treatment of tubular cells in vitro with recombinant mouse FXII induced tubular injury markers and inflammasome activation. These effects were abolished by uPAR blockade. Treatment of Wt mice with established dNP with vivo morpholino against FXII stopped progression of the disease and improved kidney functions.
Conclusions: Coagulation FXII signaling via uPAR triggers inflammasome activation and renal damage in diabetic mice. Inhibition of FXII may be a promising therapeutic approach to prevent activated inflammasome signaling in dNP and to halt the progression of the disease.
To cite this abstract in AMA style:Elwakiel A, Shahzad K, Rana R, Gupta D, Gadi I, Kohli S, Renné T, Isermann B. Coagulation Factor XII Signaling Triggers Inflammasome-associated Renal Damage in Diabetic Nephropathy [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/coagulation-factor-xii-signaling-triggers-inflammasome-associated-renal-damage-in-diabetic-nephropathy/. Accessed January 27, 2022.
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