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Abstract: TH-OR01

Heart-Specific LIM Protein (CSRP3) as a Novel Cardiorenal Connector in Acute Cardiorenal Syndrome-Related CKD Progression

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Funahashi, Yoshio, Oregon Health & Science University, Portland, Oregon, United States
  • Hutchens, Michael, Oregon Health & Science University, Portland, Oregon, United States
Background

Cardiorenal syndrome type 1 (CRS1) is acute kidney injury (AKI) caused by acute cardiovascular disease. Our translational CRS1 model, cardiac arrest and cardiopulmonary resuscitation (CA/CPR) causes AKI-CKD transition characterized by reduced GFR, increased fibrosis, renovascular hypertrophy, and elevated blood pressure-- CRS1-induced AKI-CKD (CRACKD). Heart specific LIM protein (CSRP3) is secreted into blood stream by acute cardiac injury, and taken up by renal proximal tubular cells via megalin mediated endocytosis. We hypothesized that cardiac CSRP3 mediates CRACKD.

Methods

We generated inducible cardiac CSRP3 KO mice (iCSRP3KO, csrp3 flfl/myh6 cre-esr1). CA/CPR (8min cardiac arrest) or 8min ischemia reperfusion injury (IRI) was performed to C57BL6 mice, inducible proximal tubules megalin KO mice (iMegKO), or iCSRP3KO mice. IRI mice were injected 5ug CSRP3 or PBS. GFR, αSMA expression, and renovascular wall thickness were analyzed at 49 days. Research-designated human kidney proximal tubular epithelial cell (PTEC) was used in vitro.

Results

iCSRP3KO mice did not express CSRP3 in myocardium. SnRNA sequencing of CA/CPR kidney and bulk RNA sequencing of CSRP3 treated PTEC demonstrated similar alteration of fibrosis and myogenesis related genes. CSRP3-treated IRI mice (CSRP3-IRI) demonstrated reduced GFR (785.0±96.6 vs 933.3±148.6 (µg/min/100g), p<0.05), increased fibrosis (VαSMA/Vkidney: 2.37±0.99 vs 1.43±0.40, p<0.05) and renovascular hypertrophy (thickness index: 0.61±0.03 vs 0.50±0.03, p<0.01) compared with PBS-treated IRI mice. These CSRP3 induced phenotypic changes were attenuated by pharmacological megalin inhibition in CSRP3-IRI mice or iMegKO-CA/CPR mice. Compared with littermate control, deletion of cardiac CSRP3 ameliorated CA/CPR induced GFR loss (845.4±75.6 vs 723.3±75.5, p<0.05) and BP elevation (122.8±13.3 vs 145.1±15.7 (mmHg), p<0.05). (Mean+/-SD, Student's t-test)

Conclusion

Cardiac CSRP3 mediates renal fibrosis and myogenesis leading to CRACKD. We report a novel mechanism of CRS1 induced AKI-CKD transition.

Funding

  • Veterans Affairs Support