ACE inhibition has adverse renal effects during dietary sodium restriction in proteinuric and healthy rats

Abstract

Angiotensin-converting enzyme inhibitors (ACEi) provide renoprotection. A low sodium diet enhances their efficacy. However, the added effect of sodium restriction on proteinuria and blood pressure is not invariably associated with better preservation of renal morphology, suggesting that the combination of ACEi with a low sodium diet can elicit renal structural abnormalities. To test this hypothesis, the effects of ACEi in combination with a control (CS) or a low sodium (LS) diet were investigated in healthy rats and in adriamycin nephrotic rats. After 3 weeks of treatment, rats were sacrificed and kidneys examined for renal structural abnormalities. In healthy rats, ACEi reduced blood pressure: the fall in blood pressure was significantly greater in the ACEi/LS group. Renal morphology was normal in the ACEi/CS group but severe interstitial damage was found in the ACEi/LS group. This was associated with increased interstitial macrophage influx and up-regulation of osteopontin, alpha-smooth muscle actin, and collagen III expression. In addition, ACEi/LS induced an increase in the total medial area of afferent arterioles. In nephrotic rats, ACEi/LS reduced both blood pressure and proteinuria, whereas only blood pressure was reduced in the ACEi/CS group. Mild interstitial damage was present in the ACEi/CS group but, strikingly, pronounced tubulo-interstitial abnormalities occurred in the ACEi/LS group, similar to those seen in ACEi/LS healthy rats, with similar changes in afferent arteriolar walls. In conclusion, the combination of ACEi/LS elicits pronounced renal interstitial abnormalities in healthy and nephrotic rats, despite a significant reduction of proteinuria in the latter. Considering their occurrence in healthy rats, these renal adverse effects cannot be due to specific characteristics of adriamycin nephrosis. Further studies should elucidate the mechanisms underlying these observations and their impact on long-term renoprotection.

AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease

“…Both drugs did not reduce the increased interstitial volume caused by renal ablation. This is in line with our previous work demonstrating that RAS blockade decreases glomerular damage but is less efficient with regard to interstitial injury (13)(14). Whether RAS blockade induced regression of renal injury or delayed progression of CKD in this study remains elusive.…”

c-Jun NH2-Terminal Kinase Is Crucially Involved in Renal Tubulo-Interstitial Inflammation

“…JNK activation did not significantly correlate with proteinuria; this may be explained by the diversity of the population (which was analyzed across diseases) and by many patients being on antiproteinuric treatment, possibly dissociating the amount of proteinuria from the ongoing intrarenal pathophysiological processes. In line with the latter assumption, in animal models dissociation between reduction of proteinuria and ongoing tubulo-interstitial damage has been demonstrated during antiproteinuric therapy (Hamming et al, 2006). JNK activation was generally more prominent in tubular than in glomerular cells, moreover, tubular JNK activation was stronger associated with the severity of renal damage.…”

Effects of Dietary Sodium and Hydrochlorothiazide on the Antiproteinuric Efficacy of Losartan

“…The assumption of a J curve for renoprotection is supported by animal studies. 30 However, for proteinuria, there is no evidence of a J curve, and the target should be Ͻ1 g/d. 31 Several measures can maximize the effects of RAAS blockade.…”