Genetic susceptibility to hypertension-induced renal damage in the rat. Evidence based on kidney-specific genome transfer.

Abstract

To test the hypothesis that genetic factors can determine susceptibility to hypertension-induced renal damage, we derived an experimental animal model in which two genetically different yet histocompatible kidneys are chronically and simultaneously exposed to the same blood pressure profile and metabolic environment within the same host. Kidneys from normotensive Brown Norway rats were transplanted into unilaterally nephrectomized spontaneously hypertensive rats (SHR-RT1.N strain) that harbor the major histocompatibility complex of the Brown Norway strain. 25 d after the induction of severe hypertension with deoxycorticosterone acetate and salt, proteinuria, impaired glomerular filtration rate, and extensive vascular and glomerular injury were observed in the Brown Norway donor kidneys, but not in the SHR-RT1.N kidneys. Control experiments demonstrated that the strain differences in kidney damage could not be attributed to effects of transplantation-induced renal injury, immunologic rejection phenomena, or preexisting strain differences in blood pressure. These studies ( a ) demonstrate that the kidney of the normotensive Brown Norway rat is inherently much more susceptible to hypertension-induced damage than is the kidney of the spontaneously hypertensive rat, and ( b ) establish the feasibility of using organ-specific genome transplants to map genes expressed in the kidney that determine susceptibility to hypertensioninduced renal injury in the rat. ( J. Clin. Invest. 1997. 100: 1373-1382.)

Mapping genetic determinants of kidney damage in rat models

“…169 St Lezin et al 170 assumed that underlying genetic susceptibility factors, that is, the Rf loci on RNO1, which were originally identified in the FHH rat, 77,89,90 may contribute to renal failure in BN. 170 Subsequently, the authors introgressed a 22-cM segment of RNO1, which may overlap with Rf-2, Bpfh-1 and possibly with Rf-1 in FHH, 77,89,90 from normotensive BN/Cr rats into the hypertensive SHR/Ola background of the congenic strain SHR.BN-D1Mit3/Igf2 (Tables 2 and 3).…”

Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

“…This animal exhibits impaired renal autoregulation and severely diminished afferent arteriolar myogenic reactivity, although TGF is reported to be intact (160 -162). The Brown Norway rat (BNR) also exhibits impaired myogenic responses, but does not develop hypertensive renal injury because it normally exhibits a relatively low BP (33,164). However, as elegantly shown by Churchill et al (33), when exposed to hypertension by transplantation into the SHR, the BNR kidneys develop substantially more severe injury compared with the SHR kidneys.…”

“…In the rat remnant kidney model, hypertension develops following conventional 5/6 renal ablation by infarction, but not when renal mass is reduced by surgical excision (16,58,61). In the BNR, BP is not only typically reduced, but manipulations, such as DOCA/ salt, have minimal effects (33). Similarly, there is no evidence to date of detectable disturbances in volume homeostasis in the murine gene-deletion models lacking TGF (e.g., Ref.…”

Hypertension and Chronic Kidney Disease: Cause and Consequence – Therapeutic Considerations

“…Early studies from animal models with Dahl salt-sensitive rats, Spontaneous Hypertensive Rats, Fawn-hooded rats and Brown and Norway rats as well as the results of the AASKD trial suggested a genetic susceptibility to hypertensive vascular damage (Brown et al, 1996;Churchill et al, 1997;Freedman et al, 1998;Zarif et al, 2000;Agodoa et al, 2001). Several genetic alterations have been associated to a more rapid decline of renal function in AfricanAmerican patients with hypertensive nephrosclerosis.…”