A murine model of cardiovascular-kidney-metabolic syndrome demonstrates compromised limb function in the ischemic hind limb

Abstract

AbstractsO_ST_ABSBackgroundC_ST_ABSCardiovascular-Kidney-metabolic (CKM) syndrome is a public health problem involving > 90% of the US and results in premature CVD at a relatively preserved GFR. The molecular mediators of CKM are poorly understood, partly due to the lack of a reliable animal model. We set out to generate an animal model with renal and metabolic dysfunctions, using PAD as a CKM manifestation. MethodsA group of C57BL/6 mice was randomized into four groups-a normal diet (ND), a 0.2% adenine diet (AD, a CKD model), a high-fat diet (HFD, a metabolic model), and a combination of HFD+AD (a potential CKM model). Mice underwent a hind limb ischemia surgery. An array of structural (capillary density, soleus muscle evaluation), and functional assays were performed. ResultsCompared to ND mice, AD mice showed loss of weight (40%) and GFR (90%) (P<0.001). The HFD+AD mice had 23-50% higher weight and GFR than the AD group (P = 0.003). The kidneys of HFD+AD showed tubular atrophy, tubulointerstitial fibrosis, immune infiltration, glomerulomegaly, consistent with glomerular hyperperfusion, hypercholesterolemia, impaired glucose tolerance, and adipophilin in the liver, an early marker of hepatic steatosis, and myocardial fibrosis. Compared to ND mice, the AD and HFD+AD mice showed similar reductions in the hind limb perfusion ratios, microcapillary density, Type II muscle fibers, and increased muscle fibrosis, immune infiltration, and lowest cross-sectional muscle area. Compared to AD, HFD+AD mice showed a lower flux ratio and grip strength, all at a GFR double that of the AD group. ConclusionA combination of HFD+AD in mice displays features of CKD (loss of GFR, renal fibrosis), dysfunctional obesity (dyslipidemia, impaired glucose tolerance, hepatic steatosis and glomerulomegaly), and cardiovascular disease (myocardial fibrosis and PAD) at a higher GFR, consistent with the features of CKM. This model can be explored to probe the mechanisms of CKM syndrome.