Blood Pressure-Independent Additive Effects of Pharmacologic Blockade of the Renin-Angiotensin and Endothelin Systems on Progression in a Low-Renin Model of Renal Damage

Abstract

ABSTRACT. Pharmacologic blockade of the renin and endothelin (ET) systems is an established strategy to interfere with progression of renal failure. In the Heyman nephritis model, additive benefits of decreases in BP with the combination of angiotensin-converting enzyme inhibitors (ACE-i) and ETAreceptor antagonists (ET-RA) were demonstrated. To further investigate these findings and to exclude confounding effects of BP decreases, this issue was reassessed in a low-renin model of subtotal kidney resection. Subtotally nephrectomized (SNX) and sham-operated rats were left untreated or received an ACE-i, an angiotensin II subtype 1 receptor antagonist (AT1-RA), an ET-RA, or combinations thereof (ACE-i plus ET-RA or AT1-RA plus ET-RA). The parameters studied were the glomerulosclerosis index (GSI), tubulointerstitial index, vascular damage index, glomerular geometry, and albumin excretion. After 12 wk, BP values were comparable. Urinary albumin excretion rates were significantly higher for untreated SNX rats (24.3 ± 31.3 mg/24 h), compared with untreated sham-operated rats (0.71 ± 0.40 mg/24 h). Rates were significantly lower for all treated, compared with untreated, SNX groups. GSI values were significantly higher for untreated SNX rats than for untreated sham-operated rats. ACE-i caused significantly lower GSI in SNX rats (0.46 ± 0.06), compared with AT1-RA (0.60 ± 0.10) or ET-RA (0.65 ± 0.10). GSI values were significantly decreased further with ACE-i plus ET-RA (0.29 ± 0.09) or AT1-RA plus ET-RA (23 ± 0.05) treatment. Changes in the tubulointerstitial index and vascular damage index proceeded in parallel. The results document BP-independent effects of the ACE-i and AT1-RA on the GSI and urinary albumin excretion and an effect of the ET-RA on the GSI. The contrasting results suggest different pathogenetic pathways for glomerulosclerosis and albuminuria. The combination of treatments provided superior effects on the GSI and tubulointerstitial index but not on urinary albumin excretion.

Mechanism of protective actions of sparsentan in the kidney: lessons from studies in models of chronic kidney disease

“…The concept of dual inhibition of Ang II and ET-1 as nephroprotection has been developing since the 1990s [100,101]. Studies in rodent models have included a passive Heymann nephritis model of idiopathic membranous nephropathy [101] and subtotal nephrectomy [102], a hypertension model involving 5/6 nephrectomy with overexpression of the renin gene [103], and models of diabetic nephropathy [52,61,101]. Across these studies, combining a RASi (using an ARB or ACEi) with an ERA was more effective than monotherapy in attenuating the development and progression of proteinuria, glomerular and tubulointerstitial structural changes, functional deterioration, and molecular changes characteristic of progressive CKD.…”