ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: TH-PO970

Circulating Exosomes Mediate Inter-Organ Communication in Type 2 Cardiorenal Syndrome

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Wang, Cong, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • Zhou, Lili, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • Liu, Youhua, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Inter-organ crosstalk plays an essential role in regulating tissue homeostasis, injury repair and the pathogenesis of multi-organ dysfunction. Cardiorenal syndrome type 2 (CRS2) is characterized by chronic abnormalities in cardiac function causing progressive chronic kidney disease (CKD). However, the mediators connecting heart and kidney are poorly characterized. In this study, we report that exosomes produced by injured heart plays a vital role in mediating cardiorenal connection in mouse model of transverse aortic constriction (TAC).

Methods

Four weeks after TAC, mice were randomized into three groups: 1) sham control; 2) TAC mice; 3) TAC mice injected daily with cyclopamine (CPN), a specific small molecule inhibitor of hedgehog signaling. At 8 weeks after TAC, all animals were sacrificed. Urine, blood, heart and kidney tissues were collected for analysis. Exosomes were isolated from mouse serum, and incubated with normal rat kidney interstitial fibroblast (NRK-49F) cells.

Results

At 8 weeks after TAC, cardiac hypertrophy and fibrosis were prominent, as evidenced by increased expression of β-myosin heavy chain, α-actin and fibronectin. Echocardiography also revealed an impaired cardiac function in TAC mice. These cardiac lesions were accompanied by an upregulation of sonic hedgehog (Shh) and increased production of exosomes in cardiac tissue. Blockade of Shh signaling by CPN ameliorated cardiac injury and restored heart function. Notably, TAC mice also developed kidney lesions secondary to chronic heart failure, manifested by proteinuria, kidney fibrosis and renal upregulation of Shh. CPN mitigated all these lesions in the kidneys. Serum derived from TAC mice was able to induce renal interstitial fibroblast activation in vitro, indicating the circulating factors as mediators of cardiorenal connection. Furthermore, exosomes isolated from TAC serum was sufficient to cause fibroblast activation and matrix production. Western blot demonstrated the presence of Shh and Smo in the isolated exosomes from TAC serum, but not in the exosomes from the control serum.

Conclusion

These studies demonstrate that heart-derived, circulating exosomes are a unique and effective vehicle to deliver Shh to the kidney after TAC. Targeted inhibition of Shh signaling could be a promising therapeutic strategy for protecting both heart and kidney in cardiorenal syndrome.

Funding

  • Government Support - Non-U.S.