Cardio‐Renal Syndrome Type 2: The Role of the Cardiac Spinal Afferent Reflex

Abstract

BackgroundCardio‐renal syndrome type II (CRS II) is defined as a chronic abnormality in cardiac function (chronic heart failure, CHF) causing progressive and potentially permanent chronic kidney disease. We hypothesized that the cardiac sympathetic afferent reflex (CSAR, a cardiogenic sympatho‐excitatory reflex mediated by spinal afferents from the heart) plays a critical role in the pathological development of CRS II. Specifically, we proposed that the CSAR control of sympathetic outflow to the kidneys exacerbates renal hypoperfusion and accelerates renal dysfunction including renal tubular damage in CRS II.MethodsWe examined the effects of acute or chronic activation/inhibition of the CSAR on renal blood flow (RBF), renal vascular resistance (RVR) and renal function in sham‐operated and myocardial infarction (MI) rats. Renal function was evaluated by measuring 1) blood creatinine and blood urea nitrogen (BUN) by iSTAT analysis; 2) urinary kidney damage markers such as the kidney injury molecule [KIM]‐1 and 3) RNA sequencing analysis (RNA‐Seq) in renal tissues.ResultsAcute CSAR activation by epicardial application of bradykinin (BK) in anesthetized, vagotomized rats resulted in an augmented increases in blood pressure, heart rate, and renal sympathetic nerve activity in MI compared to sham rats. CSAR activation also increased renal vascular resistance (RVR) to a greater extent in MI rats compared to sham rats. Chronic CSAR ablation by epicardial application of the highly specific TRPV1 receptor agonist resiniferatoxin (RTX) restored, in part, the decreased RBF and increased RVR in MI rats. Furthermore, epicardial RTX prevented the development of renal dysfunction at 4–5 months post MI as evidenced by decreased blood creatinine and BUN in MI+RTX rats. RNA‐Seq analysis showed that several renal injury and inflammatory gene markers were significantly upregulated by 30–100 fold at 18‐weeks post‐MI. Of those, the gene expression of KIM‐1 (a specific proximal tubular damage marker) was increased by ~70 fold in whole‐kidney tissue of MI rats compared to sham rats, whereas it was only increased by ~4 fold in rats treated with RTX. Compared to sham rats, MI rats exhibited much higher concentration of urinary Kim‐1 18 weeks post MI, which was largely prevented by RTX treatment.ConclusionThese data suggest that CSAR ablation by RTX may impart a selective protective effect on renal proximal tubular damage in CHF. Considering the fact that renal proximal tubules are located in the renal cortex where the majority of renal blood flow is distributed, it is very likely that chronic CSAR ablation improves renal proximal tubular damage by partially restoring cortical blood flow in CHF.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.