Résumé
Abstract
Background and Aims
Chronic kidney disease (CKD) is predicted to become the 5th leading cause of death by 2040. Current treatment of CKD mostly relies on non-specific therapies targeting hypertension (RASi, inhibitors of the renin angiotensin system) or blood glucose elimination (SGLT2i, inhibitors of SGLT2) that positively affect intrarenal hemodynamic. CKD progression is associated with kidney fibrosis. Successfully preventing and reversing renal fibrosis should be complementary to currently available therapies. Dimethylaminoparthenolide (DMAPT, a water-soluble form of parthenolide) is a sesquiterpene lactone with anti-inflammatory and anti-tumour activity. It has previously been shown to protect from diabetic kidney disease in mice [1]. We tested the hypothesis that DMAPT could prevent kidney fibrosis in a rat model of surgically induced CKD and aimed to compare DMAPT with the currently used therapies, Ramipril (RASi) and Dapagliflozine (SGLT2i).
Method
Eight-week-old Sprague-Dawley rats underwent subtotal nephrectomy (SNx, n = 34) or Sham surgery (Sham group, n = 8). After 1 week of recovery, SNx rats where treated with placebo (SNx group, n = 12), DMAPT at 10 mg/kg/day (DMAPT group, n = 12) or Ramipril at 10 mg/kg/day and Dapagliflozine at 1 mg/kg/day (RD group, n = 10) in the food for 7 weeks. At the end of the protocol, transdermal glomerular filtration rate (GFR, Medibeacon device) and arterial blood pressure were measured before blood, urine and organs (kidney, heart) sampling. Plasma creatinine and urea (Epoc instrument), albuminuria (ELISA kit), Sirius Red, Periodic Acid Schiff (PAS) and Collagen I immunohistochemistry (IHC) stainings in kidney, were determined, as well as mRNA expression of pro-inflammatory (Mcp1, Il1β) and kidney injury markers (Kim-1, Lcn2). Data were analysed with one-way ANOVA followed by Tukey's post hoc tests comparing groups two by two.
Results
GFR was reduced whereas plasma creatinine and urea concentrations were increased in SNx group versus Sham (P < 0.001) and treatments with DMAPT or Ramipril + Dapagliflozine did not improve these parameters versus SNx (Table 1). Urine albumin-creatinine ratio was increased in SNx (versus Sham, P = 0.0038) and reduced by Ramipril + Dapagliflozine (RD vs Sham, P = 0.0099). Higher systolic arterial pressure (P = 0.0572) and left ventricle weight (indexed to tibia length, P = 0.0336) were seen in SNx (vs Sham), and the values were normalised after treatment with Ramipril + Dapagliflozine (P = 0.0358 and 0.0021, respectively) (Table 1). Treatment with DMAPT decreased Sirius Red (P = 0.0020), PAS (P = 0.009) and Collagen I IHC (P = 0.0012) stainings in kidney, versus SNx (Fig. 1a–d). Similar tendencies were observed in RD group but with lower statistical significance (P = 0.0213, P = 0.0657 and P = 0.0793 for Sirius Red, PAS and Collagen I, respectively). Finally, DMAPT reduced the mRNA expression of pro-inflammatory cytokines Mcp1 (P = 0.0091) and Il-1β (P = 0.0551) whereas Ramipril + Dapagliflozine decreased expression Il-1β (P = 0.0543) and of kidney injury markers such as Kim-1 (P = 0.0050) and Lcn2 (P = 0.0340) (Fig. 1e).
Conclusion
Arterial pressure increase and left ventricle hypertrophy, typically observed in the SNx rat model, were normalised by Ramipril + Dapagliflozine treatment but unchanged by DMAPT treatment. Interestingly, in presence of hypertension, DMAPT treatment reduced kidney fibrosis (Sirius Red and Collagen I IHC stainings), glomerulosclerosis (PAS staining) and expression of pro-inflammatory cytokines (Mcp1, Il-1β). DMAPT is a promising anti-fibrotic compound for the treatment of CKD, complementary to existing therapies.