Premenopausal females are less susceptible than men to hypertensive renal disease 
and heart disease 
. However, after menopause the incidence of chronic renal disease in women increases suggesting that the loss of sex hormones contributes to the development and progression of kidney disease 
. This is supported by some experimental data. In studies using ovariectomized Dahl-S rats as an animal model of surgically-induced postmenopausal salt-sensitive hypertension, 17β-estradiol attenuated age-related renal dysfunction 
. However, studies of hormone replacement therapy in aging women are controversial, with some studies showing improvement 
and others showing loss of kidney function 
Our studies in premenopausal, premenopausal-ovariectomized and spontaneously postmenopausal female rats clearly show that hypertensive kidney disease or nephrosclerosis, measured as glomerular injury score, is more severe in postmenopausal and ovariectomized rats compared with premenopausal rats concordant with higher blood pressure levels detected in postmenopausal rats when compared with premenopausal rats 
. These results confirm differential pathogenesis of hypertension and its end-organ diseases in premenopausal and post menopausal states, as well as corroborate the role of ovarian hormones in postmenopausal hypertension–protective role(s) for blood pressure and for hypertensive renal disease. These observations are concordant with the studies reporting that estrogen/progestin replacement therapy improved renal function 
The identification of five distinct QTLs affecting renal disease in postmenopausal rats but which were not detected in premenopausal 
and premenopausal ovariectomized F2[Dahl S x R]-intercross rats 
demonstrate distinct pathogenetic mechanisms involved in development and progression of kidney disease in postmenopausal rats. These observations also indicate complex roles of sex hormones in postmenopausal female heath, and that given the known complexity of aging mechanisms, hormone replacement for postmenopausal hypertension and its complications would likely not suffice for projected restorative efficacy.
In three out five GIS-QTLs detected in postmenopausal rats the S allele decreased susceptibility to hypertensive glomerulosclerosis. In contrast, in both premenopausal 
and ovariectomized 
cohorts the S allele increased susceptibility to kidney disease. Analysis of reported QTLs affecting glomerulosclerosis in other Dahl S intercrosses using different normotensive strains revealed that GIS-pm2
chromosomal regions overlapped with QTLs affecting glomerular injury in a premenopausal female F2[Dahl S x Brown Norway]intercross rat cohort 
, however the directionality of the GIS-pm4
S allele effect on renal disease differed with the S allele decreasing susceptibility in our postmenopausal cohort and increasing susceptibility in the premenopausal F2[Dahl S x Brown Norway]intercross rat population 
. This suggests that the gene underlying GIS-pm2
might affect glomerulosclerosis independently of environment and age, in contrast to the gene accounting for GIS-pm4
which appears to affect renal disease in an environment and age-dependent manner. Identification of corresponding gene variants will be necessary to verify this hypothesis.
Candidate gene analysis encompassing ±15 Mbp from the peaks of GIS QTLs detected with significant and highly significant linkage revealed several candidate genes. For GIS-pm1
on chromosome 4 Adcyap1r1 (adenylate cyclase activating polypeptide 1 receptor 1) gene is located at Chr4-84.2 Mbp. For GIS-pm2
QTL peak on chromosome 3 Avp (arginine vasopressin) gene localizes to Chr3-118.2 Mbp and for GIS-pm3
the CYP4A gene cluster (Chr5-135.5 Mbp) and Edn2 (endothelin 2) at chr5-140.7 Mbp are possible candidates. Interestingly, Adcyap1r1 (also known as PAC1 receptor) and its ligand (PACAP) are present in kidney, mainly on tubular epithelial cells 
. The PAC1R/PACAP system has been associated with tubuloprotective effects in the kidney 
. Avp mapping to GIS-pm2
is a potential candidate based on its well known relationship to chronic kidney disease 
. On the other hand, the CYP4A gene cluster has been shown to affect renal injury in male congenic Dhal S rats introgressed with the chromosome 5 CYP4A region of Lewis rats 
and Edn2 has been implicated in feline naturally occurring renal failure 
and in development of glomerulosclerosis in transgenic rats expressing the human Edn2 
, thus both genes could be candidates that might underlie the effect of GIS-pm3
on hypertensive nephrosclerosis as represented in GIS measures.
In conclusion, our study demonstrates the involvement of distinct genetic mechanisms in premenopausal and postmenopausal hypertensive renal disease, and confirms the paradigm that differential genetic mechanisms underlie hypertension and its different target-organ complications in both premenopausal and postmenopausal states. These observations imply that treating hypertension resulting in the lowering of blood pressure does not necessarily address hypertensive target organ complications since the latter have distinct genetic mechanisms as demonstrated by different QTLs. The elucidation of distinct genetic mechanisms in premenopausal and postmenopausal hypertension as well as in hypertensive end organ diseases establishes a primary etiological framework for novel prevention and intervention strategies that needs to be studied further.
Altogether, these data mandate that the study of hypertension genes requires stage specific analyses for female hypertensives. Given that current anti-hypertensive therapies and prevention strategies have not eradicated hypertension nor adequately addressed postmenopausal hypertension, studies of postmenopausal hypertension and end-organ diseases need to be prioritized, if not mandatory, especially since hypertension remains a major risk factor for heart disease, kidney disease and stroke, which combine to be the number-one causes of mortality and morbidity in females.