Renal (pro)renin receptor upregulation in diabetic rats through enhanced angiotensin AT₁ receptor and NADPH oxidase activity

Abstract

Recent studies have demonstrated the presence of the (pro)renin receptor (PRR) in the glomerular mesangium and the subendothelial layer of the renal arteries. We hypothesized that diabetes upregulates PRR expression through enhanced angiotensin subtype 1 (AT 1 ) receptor-NADPH oxidase cascade activity. Using real-time polymerase chain reaction, Western blot analysis and immunostaining, we studied renal localization of the PRR in the streptozotocin-induced diabetic rat model and in response to 1 week of treatment with the AT 1 receptor blocker valsartan (10 mg kg −1 day −1 ), the angiotensin AT 2 receptor blocker PD123319 (0.5 mg kg −1 day −1 ) or the NADPH oxidase inhibitor diphenylene iodonium (DPI; 0.5 mg kg −1 day −1 ) 6 weeks post-induction of diabetes. Both PRR mRNA and protein were expressed constitutively in the kidneys of normal rat renal cortex and medulla, mainly in glomerular mesangium, proximal, distal and collecting tubules. Compared with normal rats (100%), diabetic rats demonstrated an increase in renal PRR mRNA (184%), protein (228%) and immunostaining. Valsartan and DPI prevented the increase in the PRR mRNA (106 and 126%, respectively), protein (97 and 140%, respectively) and immunostaining that was seen in the kidneys of diabetic rats. The AT 2 blocker PD123319 did not have significant effects on PRR mRNA (157%) or protein expression (200%) in the kidneys of diabetic rats. These results demonstrate that the PRR is constitutively expressed in renal glomeruli and tubules. Expression of the PRR is upregulated in diabetes via enhancement of AT 1 receptor-NADPH oxidase activity.

Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

“…In addition, the release of prorenin into the circulation may have been elevated in the diabetic rats. Thus, receptor-bound prorenin may be elevated by an increase in prorenin levels and/or an increase in (P)RR levels, 13 thereby contributing to the development of nephropathy in diabetic animals. These findings were recently confirmed by Matavelli et al 14 The direct administration of HRP to the renal cortical interstitium of diabetic rats significantly decreased urinary albumin excretion and the renal production of tumor necrosis factora and interleukin-1b.…”

Signal transduction of the (pro)renin receptor as a novel therapeutic target for preventing end-organ damage

“…15 In this regulatory context, it is of interest to note that diabetic rats exhibit an approximately twofold increase in renal (P)RR expression on mRNA and protein levels compared with normal rats. 18 Interestingly, valsartan prevented this increase by interfering with the AT1R and the downstream NADPH oxidase. 18 BIOMEDICAL RELEVANCE OF THE (P)RR Developmental biology It has already been shown in 2005 that a monogenic defect in the gene encoding the (P)RR can be the cause for X-linked mental retardation associated with epilepsy in humans.…”

“…18 Interestingly, valsartan prevented this increase by interfering with the AT1R and the downstream NADPH oxidase. 18 BIOMEDICAL RELEVANCE OF THE (P)RR Developmental biology It has already been shown in 2005 that a monogenic defect in the gene encoding the (P)RR can be the cause for X-linked mental retardation associated with epilepsy in humans. 9 Consistent with this observation, (Pro)renin receptor as novel therapeutic target H Funke-Kaiser et al the gene encoding (P)RR has a crucial role in zebrafish brain development.…”

Biochemical, Structural and Pathophysiological Aspects of Prorenin and (Pro)renin Receptor

“…Thus, (P)RR in the heart can act as a capturing molecule for renin/prorenin which ultimately explain the presence of local renin-angiotensin system in heart, which can't synthesize renin. In diabetes, enhanced activity of oxidative stress and AT1 receptor are associated with up-regulation of (P)RR and this could be suppressed using AT1 receptor blocker and NADPH-oxidase activity inhibitor (Siragy and Huang, 2008). (P)RR mediated stimulation of signal cascade (depicted in Figure 3) of transforming growth factor-1 (TGF-1) and connective tissue growth factor (CTGF) in renal glomeruli (Huang et al, 2011) and enhancement of renal production of the inflammatory cytokines-TNF-alpha and IL-1beta, independent of the effects of renal Ang-II (Matavelli et al, 2010), contributes to the development and progression of kidney disease in diabetes.…”

“…damage after being taken up by tissues from circulation. (P)RR is up-regulated in kidneys of diabetic rats and renal mesangial cells exposed to high glucose concentration (Siragy and Huang, 2008;Huang and Syragi, 2010). Rapid phosphorylation at the serine residues of (P)RR in response to hyperglycemia up-regulates TGF-beta1-CTGF cascade (Huang et al, 2011), which initiates or augments kidney disease in diabetic rats.…”