Activation of renal angiotensin type 1 receptor contributes to the pathogenesis of progressive renal injury in a rat model of chronic cardiorenal syndrome

Abstract

Although chronic cardiac dysfunction is known to progressively exacerbate renal injury, a condition known as type 2 cardiorenal syndrome (CRS), the mechanism responsible is largely unknown. The present study was undertaken to clarify the mechanism of renal injury in rats with both unilateral nephrectomy (NX) and surgically induced myocardial infarction (MI), corresponding to a model of type 2 CRS. Compared with a control group, rats with both MI and NX (MI+NX) exhibited progressive proteinuria during the experimental period (34 wk after MI surgery), whereas proteinuria was not observed in rats with MI alone and was moderate in rats with NX alone. The proteinuria in rats with MI+NX was associated with renal lesions such as glomerulosclerosis and infiltration of mononuclear cells and upregulation of the renal proinflammatory and -fibrotic cytokine and angiotensin II type 1a receptor (AT1aR) genes. In contrast, plasma renin activity was lowered in rats with MI+NX. Immunohistochemistry revealed that the increased AT1R protein was present mainly in renal interstitial mononuclear cells. Olmesartan medoxomil, an AT1R blocker, markedly reduced the proteinuria and infiltration of mononuclear cells, whereas spironolactone, a mineralocorticoid receptor blocker, did not. The present findings demonstrate the pathogenetic role of renal interstitial AT1R signaling in a model of type 2 CRS, providing evidence that AT1R blockade can be a useful therapeutic option for this syndrome.

Angiotensin II Receptor Blocker Attenuates Intrarenal Renin-Angiotensin-System and Podocyte Injury in Rats with Myocardial Infarction

“…In good agreement with other observations [1,8,9], the present study has shown that common renal damage after MI could be significantly prevented by RAS intervention, such as with the use of losartan. Furthermore, increased inflammatory cell infiltration and fibrosis within the kidneys occurring post-MI heart failure has also been demonstrated by our previous study [6] and the other study [10]. Our previous study [6] also demonstrated that increased inflammatory cell infiltration and fibrosis within the kidneys post-MI could be significantly attenuated by losartan treatment.…”

“…Renal activation of AT1R by enhanced AngII seems to be independent of systemic RAS activation and is maintained even when the systemic vascular AT1Rs are effectively blocked [10,20]. The present study demonstrates that augmentation of AngII, coupled with its receptors, increased significantly in renal cortical tissue following MI.…”

CCN1 expression in interleukin-6 deficient mouse kidney in experimental model of heart failure

“…It was suggested that AT1 receptor mediates the AngII-induced activation of nuclear factor kB in the tubular epithelium [26]. In the experimental model of chronic heart failure syndrome in rats, activation of renal AT1R was shown to contribute to the development of progressive renal dysfunction [21]. In our study blocking of AT1 receptors with telmisartan did not have prominent influence on total CCN1 protein expression in infarcted WT mice, however, telmisartan treatment attenuated CCN1 expression in the proximal convoluted tubules, which may suggest a role of angiotensin II in the expression of CCN1 in this portion of the nephron.…”

“…AT1R is expressed in all renal tubular and vascular segments and in mesangial cells [19,20]. It regulates tubular reabsorption and blood pressure, and seems to contribute to the development of renal dysfunction in cardiorenal syndrome [19,21]. It remains unknown whether AT1R mediates renal expression of CCN1and if there are alterations of renal CCN1 expression in chronic renal dysfunction related to chronic circulatory failure, which corresponds to the cardiorenal syndrome type 2.…”

Molecular Imaging of Urogenital Diseases

“…Development of glomerulosclerosis and tubulointerstitial fibrosis have been linked to age-dependent activation of the RAS which increases the risk of both AKI and CKD. Upregulation of renal AT1R has been described in animal models of hypertension ( 143 ) and cardiorenal syndrome ( 144 ), glomerulonephritis ( 145 ) subtotal nephrectomy ( 146 ). Progression of renal and cardiac failure and atherosclerotic disease are less frequent in premenopausal women than age matched men.…”