Involvement of Lysyl Oxidase in the Pathogenesis of Arterial Stiffness in Chronic Kidney Disease

• Published in: The FASEB journal Vol. 36 Suppl 1
• Main Authors: Sharma, Ravindra K, Krishnan, Suraj, Jakkidi, Nishka, Gomes, Joshua, Li, Shiyu K, Mohandas, Rajesh
• Format: Journal Article
• Language: English
• Published: United States 01.05.2022
• ISSN: 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R3425

Increased vascular stiffness is a key mediator of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Increased vascular stiffness in CKD is thought to be the consequence of long-standing hypertension and vascular calcification. However, vascular stiffness is increased early in patients with CKD, even before metabolic complications develop. Lysyl Oxidase (LOX) is a key mediator of collagen crosslinking and matrix remodeling. Up-regulation of LOX has been associated with increased tissue stiffness in cancer and wound healing. We hypothesize that increased LOX might be a key mechanism for increased vascular stiffness in CKD. β-aminopropionitrile (BAPN), a LOX inhibitor, was used to test the hypothesis. 5/6 nephrectomy (Nx) or Sham surgery was performed in 8-weeks old male C57BL/6 mice. 2-weeks after Nx, mice were randomized to BAPN (300 mg/kg/day in water) or vehicle for 4-weeks. Vascular stiffness was assessed by pulse wave velocity (PWV). LOX levels were measured by ELISA and qPCR. Collagen crosslinking was measured by mass spectrometry. Comparisons between groups were made using one-way ANOVA, p-Value <0.05 was accepted as significant. Nx resulted in decreased renal function at 8 weeks but no change in blood pressure or calcification. (~2-3-fold increase in creatinine, urea, and cystatin C) compared to control mice. Nx surgery resulted in increase in PWV (Con:179±32, Nx: 306 ± 47 cm/s, p<0.001). This was associated with an increased LOX in aorta (Con:118±8, Nx: 311±13 pg/mg dry weight, p<0.001). Mice with Nx surgery had an increased total collagen contents (183%, p<0.001) as well as cross-linked collagen (DPD; 83%, p<0.05, PYD: 270% p<0.01). BAPN treatment significantly attenuates PWV (211± 49 cm/s, p<0.01), LOX (256±21 pg/mg dry weight, p<0.05) and total collagen contents (23%, p<0.01). BAPN treatment reduced the crosslinked collagens (DPD and PYD) but this did not reach statistical significance. Our findings suggest: a) Increased vascular stiffness in CKD is independent of BP and calcification b) LOX mediated changes in extracellular matrix are at least in part responsible for the pathogenesis of arterial stiffness in CKD. Inhibition of excessive LOX may have therapeutic potential in alleviating increased vascular stiffness in CKD.