Abstract Number: OC 77.2
Meeting: ISTH 2021 Congress
Background: Diabetic nephropathy (dNP) is the leading cause of end-stage renal disease worldwide. Diabetes is associated with elevated levels of FXII. 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 unknown.
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 and maintained for 24 weeks. Kidney RNA sequencing was performed to identify involved pathways. Ex-vivo and in vitro studies were conducted to obtain mechanistic insights.
Results: Elevated levels of FXII were detected in a cohort of dNP human urine samples. Increased tubular expression of FXII was observed in human and mouse diabetic kidneys. In diabetic FXII-/- mice, albuminuria and tubulointerstitial fibrosis were ameliorated compared to diabetic WT mice. RNA sequencing identified 154 genes that were upregulated in diabetic WT mice and normalized in diabetic FXII-/- mice. Functional annotation of the differentially upregulated genes revealed pathways related to senescence. Diabetic FXII-/- kidneys showed less senescence compared to WT mice. Renal expression of urokinase‐type plasminogen activator receptor (uPAR), which is strongly induced in diabetic WT mice and has been linked to senescence, was normalized in diabetic FXII-/- mice. Recombinant FXII induced tubular cell injury and senescence in vitro by increasing uPAR expression and its signaling via β1 integrin. Treatment of WT mice with established dNP with vivo morpholino targeting FXII stopped progression and partially reversed experimental dNP.
Conclusions: Coagulation FXII signaling via uPAR triggers tubular senescence and renal damage in diabetic mice. Inhibition of FXII or the related signaling pathway could be a promising therapeutic approach to prevent senescence in dNP and to halt the progression of the disease.
To cite this abstract in AMA style:Elwakiel A, Shahzad K, Gadi I, Gupta D, Rana R, Kohli S, Renné T, Isermann B. Coagulation Factor XII Signaling via uPAR- β1 Integrin Promotes Renal Tubular Senescence in Diabetic Nephropathy [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/coagulation-factor-xii-signaling-via-upar-%ce%b21-integrin-promotes-renal-tubular-senescence-in-diabetic-nephropathy/. Accessed December 6, 2023.
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