Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver.

Véniant, Murielle M.; Ménard, Joël; Bruneval, Patrick; Morley, Steven D.; Gonzales, M. F.; Mullins, John J.

doi:10.1172/jci119000

Cited by 156 publications

(132 citation statements)

References 36 publications

(23 reference statements)

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“…In a related study, Véniant et al (37) used a conventional transgenic approach to overexpress rat prorenin in the liver of rats. Despite a 400-fold increase in plasma prorenin levels, these transgenic rats did not have elevated BP, presumably because the circulating prorenin secreted from the liver could not be cleaved in the blood stream into active renin.…”

Section: Discussionmentioning

confidence: 99%

A genetically clamped renin transgene for the induction of hypertension

Caron

James

Kim

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Experimental analysis of the effects of individual components of complex mammalian systems is frequently impeded by compensatory adjustments that animals make to achieve homeostasis. We here introduce a genetic procedure for eliminating this type of impediment, by using as an example the development and testing of a transgene for “genetically clamping” the expression of renin, the major homeostatically responding component of the renin–angiotensin system, one of the most important regulators of blood pressure. To obtain a renin transgene whose expression is genetically clamped at a constant level, we have used single-copy chosen-site gene targeting to insert into a liver-specific locus a single copy of a modified mouse renin transgene driven by a liver-specific promoter/enhancer. The resulting transgene expresses renin ectopically at a constant high level in the liver and leads to elevated plasma levels of prorenin and active renin. The transgenic mice display high blood pressure, enhanced thirst, high urine output, proteinuria, and kidney damage. Treatment with the angiotensin II type I receptor antagonist, losartan, reduces the hypertension, albuminuria, and kidney damage, but does not affect expression of the transgene. This genetically clamped renin transgene can be used in models in which hypertension and its complications need to be investigated in a high prorenin/renin environment that is not subject to homeostatic compensations by the animal when other factors are changed

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Section: Discussionmentioning

confidence: 99%

A genetically clamped renin transgene for the induction of hypertension

Caron

James

Kim

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the role of prorenin in the pathogenesis of hypertension and endorgan damage remains uncertain, 12,35 although elevated plasma prorenin concentrations have been implicated as a cause of microangiopathy in diabetic patients. 36 A newly developed transgenic rat model developed by Veniant et al 37 that overexpresses rat prorenin in the liver exhibited a 400-fold increase in plasma prorenin. The transgenic model showed cardiac hypertrophy and severe renal lesions in the absence of blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Effects of Human Prorenin in Rats Transgenic for Human Angiotensinogen

Müller

Hilgers²,

Mathews³

et al. 1999

Hypertension

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Abstract-The physiological role of prorenin is unknown; however, the possibility that prorenin inhibits renin locally has been suggested. We tested the hypothesis that prorenin may be an endogenous competitor for renin uptake in the tissue. We also investigated whether prorenin can be activated to active renin and affect mean arterial pressure (MAP). Isolated perfused hindquarters of rats transgenic for human angiotensinogen were infused with human renin and/or prorenin. The plateau phase of angiotensin (Ang) I release 15 minutes after cessation of infusions was used as a parameter for renin uptake. Renin (10 ng/mL for 15 minutes) caused sustained release of Ang I (153Ϯ16 fmol/mL). Coinfusion with a 15-fold excess of prorenin did not affect local Ang I formation (153Ϯ19 fmol/mL). Prorenin infusion alone showed no activation to active renin. In addition, we investigated MAP and plasma Ang II levels after injection of saline (⌬MAP, Ϫ1Ϯ2 mm Hg; 40Ϯ5 fmol/mL Ang II), 9 ng renin (⌬MAP, ϩ37Ϯ3 mm Hg; 378Ϯ39 fmol/mL), and 144 ng prorenin (⌬MAP, ϩ10Ϯ5 mm Hg; 61Ϯ5 fmol/mL) and the coinjection of renin and prorenin (⌬MAP, ϩ41Ϯ4 mm Hg; 305Ϯ23 fmol/mL) in anesthetized rats. The data show that prorenin was not activated to active renin and did not affect MAP in short-term experiments. Renin-induced Ang formation was not affected by prorenin. Renin may have been taken up specifically because of its physical and chemical properties or because of nonspecific sequestration in the extravascular space. We conclude that prorenin does not act as an endogenous antagonist for the long-lasting effects of renin in the vascular wall. Moreover, prorenin does not affect acute renin-related effects on blood pressure.

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“…The increase in renin activity stimulates the conversion of Ang I and ultimately Ang II, which largely limits the efficacy of RAS inhibition (27,28). The increased renin can also act through the prorenin/ renin receptor (10), which may cause renal and cardiovascular damages independent of Ang II (29). Given that low-calcemic vitamin D analogs are able to inhibit renin expression in animals (30, 31), we reasoned that combining vitamin D analogs with RAS inhibitors to suppress the reactive renin increase should generate better therapeutic effects (32).…”

mentioning

confidence: 99%

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

Zhang

Ning

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

262

225

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The renin-angiotensin system (RAS) plays a critical role in the development of diabetic nephropathy, and blockade of the RAS is currently used for treatment of diabetic nephropathy. One major problem for the current RAS inhibitors is the compensatory renin increase, which reduces the efficacy of RAS inhibition. We albuminuria ͉ glomerulosclerosis ͉ renin-angiotensin system D iabetic nephropathy is the most common renal complication that often leads to end-stage kidney disease and high mortality (1). Previous studies have suggested the renin-angiotensin system (RAS) as a major mediator of progressive renal injury in diabetic nephropathy. Drugs targeting the RAS including angiotensin (Ang)-converting enzyme inhibitors (ACEIs) and Ang II type 1 receptor blockers (ARBs) have been shown to reduce the progression of glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria (2-6). The systemic components of the RAS are actually down-regulated in diabetic mellitus (7), whereas renal interstitial Ang II levels are estimated to be 1,000-fold higher than in the plasma (8); therefore, intrarenal RAS is thought to play the major damaging role. In fact, all components of the RAS are present within the kidney (9). Cells in the kidney are able to synthesize renin, prorenin/renin receptor (10), angiotensinogen, and Ang II receptors independent of the systemic RAS (11), making the kidney capable of maintaining a high level of intrarenal Ang II. Intrarenal renin and angiotensinogen levels are induced in diabetic animals (12, 13), and high glucose has been shown to stimulate renin and Ang II synthesis in mesangial cells and podocytes (14-16). Intrarenal Ang II exerts multiple effects on the kidney that promote the progression of renal injury; these include an increase in glomerular capillary pressure, induction of profibrotic and proinflammatory cytokine production, promotion of immune cell infiltration, stimulation of cell proliferation and hypertrophy, up-regulation of extracellular matrix (ECM) synthesis, and damaging of podocytes (17)(18)(19) (21), and null mutant mice lacking the vitamin D receptor (VDR) gene develop hyperreninemia, high blood pressure, and cardiac hypertrophy (22)(23)(24). Our recent studies showed that in diabetic state VDR-null mice developed more severe nephropathy than wild-type mice (25), suggesting that vitamin D plays a protective role against hyperglycemia-induced renal injury by regulation of the RAS. However, whether vitamin D or vitamin D analogs have therapeutic effects in intervention or prevention of diabetic nephropathy remains to be tested.Although RAS inhibitors, including ACEIs and ARBs, are widely used in the therapy of renal and cardiovascular diseases, the major problem of these drugs is the compensatory renin rise due to the disruption of the feedback inhibition of renin production (26). The increase in renin activity stimulates the conversion of Ang I and ultimately Ang II, which largely limits the efficacy of RAS inhibition (27,28). The increased renin can also act through the...

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Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver.

Cited by 156 publications

References 36 publications

A genetically clamped renin transgene for the induction of hypertension

A genetically clamped renin transgene for the induction of hypertension

Effects of Human Prorenin in Rats Transgenic for Human Angiotensinogen

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

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