Abstract
Background: In renal transplantation, chronic transplant dysfunction (CTD) is associated with increased PCSK9 and dyslipidemia. PCSK9 is an enzyme that increases plasma cholesterol levels by downregulating LDLR expression. We recently showed increased PCSK9–syndecan-1 interaction in conditions of proteinuria and renal function loss. Treatment with heparin(oids) might be a therapeutic option to improve dyslipidemia and CTD. We investigated the effects of (non-)anticoagulant heparin(oids) on serum lipids, syndecan-1 and PCSK9 levels, and CTD development. Methods: Kidney allotransplantation was performed from female Dark Agouti to male Wistar Furth recipients. Transplanted rats received daily subcutaneous injections of saline, unfractionated heparin, and RO-heparin or NAc-heparin (2 mg heparin(oid)/kg BW) until sacrifice after 9 weeks of treatment. Results: Saline-treated recipients developed hypertension, proteinuria, and loss of creatinine clearance (all p < 0.05 compared to baseline), along with glomerulosclerosis and arterial neo-intima formation. Saline-treated recipients showed significant increase in plasma triglycerides (p < 0.05), borderline increase in non-HDLc/HDLc (p = 0.051), and ∼10-fold increase in serum syndecan-1 (p < 0.05), without significant increase in serum PCSK9 at 8 weeks compared to baseline. Heparin and non-anticoagulant RO-heparin administration in transplanted rats completely prevented an increase in triglycerides compared to saline-treated recipients at 8 weeks (both p < 0.05). Heparin(oids) treatment did not influence serum total cholesterol (TC), plasma syndecan-1 and PCSK9 levels, creatinine clearance, proteinuria, glomerulosclerosis, and arterial neo-intima formation, 8 weeks after transplantation. Combining all groups, increased syndecan-1 shedding was associated with TC (r = 0.5; p = 0.03) and glomerulosclerosis (r = 0.53; p = 0.021), whereas the non-HDLc/HDLc ratio was associated with the neo-intimal score in the transplanted kidneys (r = 0.65; p < 0.001). Conclusion: Prevention of triglyceridemia by (non-)anticoagulant heparin(oids) neither influenced PCSK9/syndecan-1 nor precluded CTD, which however did associate with the shedding of lipoprotein clearance receptor syndecan-1 and the unfavorable cholesterol profile.
Highlights
Chronic transplant dysfunction (CTD) is a functional decline of the transplanted kidney characterized by a progressive increase in plasma creatinine levels, proteinuria, and hypertension (Van Timmeren et al, 2007)
These findings showed that heparins and heparinoids can interact with proprotein convertase subtilisin/kexin type-9 (PCSK9) via their negatively charged sulfated sugar groups and bear the potential to be developed as PCSK9 inhibitors for the treatment of dyslipidemia (Gustafsen et al, 2017; Shrestha et al, 2021a; Shrestha et al, 2021b)
Interventions were performed by daily (s.c.) injections of 2 mg/kg body weight (BW)/day with regular unfractionated heparin and two nonanticoagulant heparinoids derived from regular heparin: N-desulfated, N-reacetylated heparin (NAc-heparin; molecular weight (MW) 18,269 Da; n = 10) and periodate-oxidized, borohydridereduced heparin (RO-heparin; MW 16,522 Da; n = 9) as reported before by Talsma et al (2017) (Casu et al, 2004; Naggi et al, 2005)
Summary
Chronic transplant dysfunction (CTD) is a functional decline of the transplanted kidney characterized by a progressive increase in plasma creatinine levels, proteinuria, and hypertension (Van Timmeren et al, 2007). About 30–50% of renal allografts are lost after 5 years of transplantation due to CTD, making CTD a major challenge in the field of transplantation (Marcén and Teruel, 2008; Ekberg and Johansson, 2012; Lai et al, 2021) Histological changes, such as interstitial fibrosis, tubular atrophy, and vascular and glomerular occlusions, are hallmarks of a dysfunctional allograft (Nankivell et al, 2003; Van Timmeren et al, 2007). Human leukocyte antigen (HLA) mismatches between donor and recipient give rise to cytotoxic T cells, NK cells, and donor-specific antibodies, causing immune-related injury to the graft, whereas hypertension, ischemia, infections, dyslipidemia, diabetes, and drug toxicity cause non-immune-related graft injury (Nankivell et al, 2003; Najafian and Kasiske, 2008) Among these nonimmune-related factors, dyslipidemia is an important but often overlooked factor in the development and progression of CTD and cardiovascular diseases (Del Castillo et al, 2004; Luca et al, 2015; Elkins et al, 2019). We investigated the effects of (non-)anticoagulant heparin(oids) on serum lipids, syndecan-1 and PCSK9 levels, and CTD development
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