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CX3CL1 Worsens Cardiorenal Dysfunction and Serves as A Therapeutic Target of Canagliflozin for Cardiorenal Syndrome
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  • Cankun Zheng,
  • Wanling Xuan,
  • Zhenhuan Chen,
  • Rui Zhang,
  • Xiaoxia Huang,
  • Yingqi Zhu,
  • Siyuan Ma,
  • Kaitong Chen,
  • Lu Chen,
  • Mingyuan He,
  • Hairuo Lin,
  • Wangjun Liao,
  • Jianping Bin,
  • Yulin Liao
Cankun Zheng
Southern Medical University Nanfang Hospital
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Wanling Xuan
Southern Medical University Nanfang Hospital
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Zhenhuan Chen
Southern Medical University Nanfang Hospital
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Rui Zhang
Southern Medical University Nanfang Hospital
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Xiaoxia Huang
Southern Medical University Nanfang Hospital
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Yingqi Zhu
Southern Medical University Nanfang Hospital
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Siyuan Ma
Southern Medical University Nanfang Hospital
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Kaitong Chen
Southern Medical University Nanfang Hospital
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Lu Chen
Southern Medical University Nanfang Hospital
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Mingyuan He
Southern Medical University Nanfang Hospital
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Hairuo Lin
Southern Medical University Nanfang Hospital
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Wangjun Liao
Southern Medical University Nanfang Hospital
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Jianping Bin
Southern Medical University Nanfang Hospital
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Yulin Liao
Southern Medical University Nanfang Hospital

Corresponding Author:[email protected]

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Abstract

Background and Purpose The prognosis of cardiorenal dysfunction induced by diabetes mellitus (DM), which belongs to cardiorenal syndrome type 5, is poor and its pathogenesis remains elusive. Here we attempt to clarify whether CX3CL1 might be a therapeutic target for cardiorenal dysfunction in diabetes. Experimental Approach Effects of CX3CL1 on cardiorenal function, myocardial and renal fibrosis, and apoptosis were examined using four types of cultured cardiomyocytes or renal cells and two diabetic mouse models, streptozotocin-induced DM or non-obese diabetic (NOD) mice. The effect of sodium glucose cotransporter 2 inhibitor canagliflozin on CX3CL1 expression was also investigated in vivo or in vitro. Key Results Cardiac and renal CX3CL1 protein levels were significantly increased in both STZ-induced diabetic mice and NOD mice, and that hyperglycemia led to persistent CX3CL1 expression in the heart and kidneys even after it was controlled by insulin. In cultured cardiac and renal cells, soluble CX3CL1 accelerated mitochondrial-dependent apoptosis via activation of the RhoA/ROCK1-Bax pathway and promoted fibrosis through cellular phenotypic trans-differentiation mediated by the TGFβ/Smad pathway. In the two diabetic mouse models, knockout of CX3CL1 receptor CX3CR1 or treatment with an CX3CL1 neutralizing antibody significantly improved cardiorenal dysfunction by inhibiting apoptosis, mitochondrial dysfunction, and fibrosis. Moreover, sodium glucose cotransporter 2 inhibitor canagliflozin significantly downregulated cardiac and renal CX3CL1 expression and improved cardiorenal dysfunction. Conclusions and Implications These findings indicate that CX3CL1 could be a new therapeutic target for diabetes-induced cardiorenal dysfunction.