Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

Abstract

The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-b mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-b mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.

(Pro)renin and its receptors: pathophysiological implications

“…However, in apparent contrast with the above in vitro results on glucose-induced (P)RR upregulation in mesangial cells, HRP (0.2 mg/kg of body weight per day) did not suppress the elevated renal interstitial AngII in diabetic rats, nor normalized the increased (P)RR expression in this model [88]. In fact, the lack of effect of HRP on (P)RR expression appears to be a general phenomenon in in vivo studies applying this drug [76,78,[89][90][91]. AT 1 receptor blockade with valsartan did normalize (P)RR expression, and both HRP and valsartan suppressed the up-regulated TGFβ1 levels in the diabetic rat kidney [92].…”

“…HRP (3.5 μg/kg of body weight per day during 14 days) did not affect hypertensive nephrosclerosis in Goldblatt (2K1C) rats [102]. Ryuzaki et al [91], when applying HRP at 1 mg/kg of body weight per day in 2K1C rats, confirmed this finding, but simultaneously demonstrated that HRP after 12 weeks of infusion reduced the glomerulosclerosis index, tubulointerstitial damage, TGFβ1 expression and AngII levels in the nonclipped kidney (but not in the clipped kidney). Under no condition did HRP affect BP or proteinuria.…”

Chronic blockade of the (pro)renin receptor ameliorates the kidney damage in the non-clipped kidney of Goldblatt hypertension

“…In contrast, the long-term treatment with HRP prevents the glomerular and tubular damage that develop chronically in the non-clipped kidneys in the 2K1C models. In other words, the only difference between the previous report 20 and the study done by Ryuzaki et al 22 is simply in the longer duration of administration of HRP in the Goldblatt hypertensive model, which suggests that the effect of HRP was dependent on the treatment length, but not on the dosage of HRP. In contrast to aliskiren, because HRP did not reduce the blood pressure, the effect of HRP is only expected in chronic administration and therefore was not observed in the acute phase of the Goldblatt hypertensive model.…”

“…19 There is much confusion concerning the mode of action of HRP, and the basis of the discrepancy between the in vitro and in vivo data is unknown. Overall, the HRP results in the animal models were disappointing, although Ryuzaki et al 22 clearly showed beneficial effects of HRP in the two-kidneys, one-clip (2KIC) model of hypertensive nephrosclerosis in an issue of Hypertension Research. They carefully investigated the long-term effect of HRP on the slowly progressive nephropathy that occurred in the nonclipped kidney of the two-kidneys, one-clip renovascular hypertension model.…”

The (pro)renin receptor mediates constitutive PLZF-independent pro-proliferative effects which are inhibited by bafilomycin but not genistein

“…These controversies may be explained by the prorenin-renin ratio since the decoys were effective in high prorenin/low renin models (1,11), and/or by the length of treatment based on the observation that renoprotective effects were able to be observed after 12 weeks even in a high renin Goldblatt model (12,13). …”