Spatially resolved label-free FTIR imaging reveals compartment-specific spectral signatures of cardiorenal crosstalk and their pharmacological modulation by Sacubitril/Valsartan.

Cardiorenal syndrome (CRS) involves complex and spatially heterogeneous remodeling in both cardiac and renal tissues. Conventional histological and biochemical assays rely on labeling or lack direct molecular specificity, limiting their ability to capture compartment-specific remodeling. Analytical approaches that resolve localized biochemical alterations are essential to advance mechanistic insight into heart-kidney interactions. Here, Fourier-transform infrared (FTIR) micro-imaging was applied to left ventricular and renal tissues from a rat model of heart-kidney interaction, in which unilateral nephrectomy induced renal stress prior to cardiac ischemia-reperfusion injury. To address tissue heterogeneity, an analytical workflow was implemented in which unsupervised hierarchical clustering segmented spectrally homogeneous regions, followed by principal component analysis, to identify spectral markers associated of disease-related biochemical alterations. This strategy enabled identification of spatially localized spectral variations associated with disease progression. Distinct spectral signatures of tissue remodeling were identified in both organs. Cardiac perivascular regions exhibited pronounced alterations in bands at 1040, 1202, and 1232 cm-1, while renal medullary compartments displayed disease-associated variations at 1313 and 1396 cm-1 following nephrectomy. Several spectral features correlated with independent biological measures, including histologically quantified fibrosis, urinary protein excretion, and left ventricular mass. Treatment-associated spectral modulation was also observed, with animals receiving Sacubitril/Valsartan exhibited spectral intensities below pathological thresholds for the main cardiac markers, indicating partial normalization of disease-associated spectral alterations. These findings demonstrate that spatially resolved FTIR spectroscopic imaging can identify compartment-specific spectral signatures of disease progression and treatment response in experimental heart-kidney interaction.