Hummelgaard Sandra, Hvid Henning, Birn Henrik, Glerup Simon, Tom Nikola, Bilgin Mesut, Kirchhoff Jeppe Egedal, Weyer Kathrin
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Cardio-Renal Pharmacology, Novo Nordisk, Måløv, Denmark.
Am J Physiol Renal Physiol. 2025 Jan 1;328(1):F48-F67. doi: 10.1152/ajprenal.00065.2024. Epub 2024 Nov 18.
Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). Despite the entry of sodium glucose cotransporter 2 (SGLT2) inhibitors, CKD persists as a medical challenge. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces low-density lipoprotein (LDL)-cholesterol, a major risk factor of CVD. Interestingly, studies indicate that PCSK9 inhibition decreases proteinuria in kidney disease, complementing the reduced CVD risk. This study aimed to validate obese ZSF1 rats as a model for the renoprotective effects of PCSK9 and SGLT2 inhibition using alirocumab and empagliflozin for 15 wk. Obese rats revealed a significant reduction in measured glomerular filtration rate (mGFR) and increased urine albumin/creatinine ratio (UACR) during follow-up compared with lean controls. Alirocumab treatment resulted in a decline in mGFR and increased UACR compared with vehicle-treated obese rats. Immunohistochemistry showed increased fibrosis and inflammation in kidney tissue from obese rats treated with empagliflozin or alirocumab, whereas hepatic cholesterol and triglyceride levels were lowered compared with vehicle-treated obese rats. Although alirocumab lowered circulating free cholesterol levels throughout the treatment period, certain cholesteryl esters were increased at the end of the study, resulting in no overall difference in total cholesterol levels in the alirocumab group. Correspondingly, only a trend toward increased hepatic LDL-receptor levels was observed. In conclusion, these findings suggest that alirocumab treatment aggravates kidney dysfunction in obese ZSF1 rats. Moreover, in contrast to the renoprotective properties of empagliflozin observed in patients with CKD, empagliflozin did not ameliorate kidney disease progression in the obese ZSF1 rat. New treatments to slow kidney disease progression and reduce cardiovascular disease risk are needed for chronic kidney disease (CKD). We investigated the cholesterol-lowering PCSK9 inhibitor alirocumab as a new treatment for proteinuric CKD and the effect of SGLT2 inhibition using empagliflozin in obese ZSF1 rats. Regarding renoprotection, our findings were contradictory with previous preclinical studies and clinical data, suggesting that different pathophysiological mechanisms may apply to this rat model.
慢性肾脏病（CKD）与心血管疾病（CVD）风险增加相关。尽管钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂已应用，但CKD仍是一项医学挑战。前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）抑制可降低低密度脂蛋白（LDL）胆固醇，这是CVD的主要危险因素。有趣的是，研究表明PCSK9抑制可降低肾病中的蛋白尿，这与降低的CVD风险相辅相成。本研究旨在验证肥胖ZSF1大鼠作为使用阿利西尤单抗和恩格列净进行15周PCSK9和SGLT2抑制的肾脏保护作用模型。与瘦对照组相比，肥胖大鼠在随访期间测得的肾小球滤过率（mGFR）显著降低，尿白蛋白/肌酐比值（UACR）升高。与载体处理的肥胖大鼠相比，阿利西尤单抗治疗导致mGFR下降和UACR升高。免疫组织化学显示，用恩格列净或阿利西尤单抗治疗的肥胖大鼠肾组织纤维化和炎症增加，而与载体处理的肥胖大鼠相比，肝脏胆固醇和甘油三酯水平降低。尽管在整个治疗期间阿利西尤单抗降低了循环游离胆固醇水平，但在研究结束时某些胆固醇酯增加，导致阿利西尤单抗组总胆固醇水平无总体差异。相应地，仅观察到肝脏LDL受体水平有增加的趋势。总之，这些发现表明阿利西尤单抗治疗会加重肥胖ZSF1大鼠的肾功能障碍。此外，与在CKD患者中观察到的恩格列净的肾脏保护特性相反，恩格列净并未改善肥胖ZSF1大鼠的肾病进展。慢性肾脏病（CKD）需要新的治疗方法来减缓肾病进展并降低心血管疾病风险。我们研究了降胆固醇的PCSK9抑制剂阿利西尤单抗作为蛋白尿性CKD的新治疗方法以及在肥胖ZSF1大鼠中使用恩格列净进行SGLT2抑制的效果。关于肾脏保护，我们的发现与先前的临床前研究和临床数据相矛盾，表明不同的病理生理机制可能适用于该大鼠模型。
