Genetic low nephron number hypertension is associated with dysregulation of the hepatic and renal insulin-like growth factor system during nephrogenesis.
OBJECTIVE
Low nephron number may represent a major determinant of human primary hypertension in adult life. This hypothesis is supported by a genetic rat model, namely the Munich-Wistar-Frömter (MWF) rat, which demonstrates an inherited deficit in nephron number and the development of spontaneous hypertension. Insulin-like growth factor (IGF) I and II exert endocrine and paracrine effects that are required for normal growth and nephron development. We tested the hypothesis that low nephron number is already present during fetal development, and the expression pattern of important molecules of the IGF system is altered in MWF rat during the critical period of kidney development.


METHODS
We compared MWF and normal Wistar rats during nephrogenesis at day 19 of fetal development (E19) and adult rats at postnatal day 100 (D100). Histomorphometric analysis was performed by stereological methods. Quantitative messenger RNA and protein expression was determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay.


RESULTS
At E19, glomerular density (-32%) and hepatic mRNA (-48%) and protein (-18%) expression of IGF-I were decreased (P < 0.05, respectively), whereas renal mRNA expression of IGF-II receptor (+52%) and IGF binding protein 3 (+113%) were increased in MWF compared with Wistar rats (P < 0.05, respectively). Systolic blood pressure, urinary albumin excretion, and mean glomerular area were significantly elevated in MWF compared with Wistar rats at D100 (P < 0.05, respectively).


CONCLUSIONS
The fetal expression of IGF system molecules in the MWF rat model points towards a link between the decreased availability of active IGF-I and IGF-II and the fetal development of low nephron number, with manifestation of genetic hypertension in adult life.
Rothermund
Lars
L
Medizinische Klinik IV, Endokrinologie und Nephrologie, Charité Universitätsmedizin Berlin, Berlin, Germany. lars.rothermund@charite.de
Nierhaus
Marc
M
Fialkowski
Olaf
O
Freese
Florian
F
Ibscher
Ricarda
R
Mieschel
Susanne
S
Kossmehl
Peter
P
Grimm
Daniela
D
Wehland
Markus
M
Kreutz
Reinhold
R
D000818:Animals; D001835:Body Weight; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006728:Hormones / Q000378:metabolism; D006973:Hypertension / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D009399:Nephrons / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013002:Somatomedins / Q000096:biosynthesis / Q000502:physiology*
D006728:Hormones; D012333:RNA, Messenger; D013002:Somatomedins