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1 Chair of Nephrology and Research Center for Cardiovascular Diseases, Faculty of Medicine, Second University of Napoli, Naples, Italy
2 Sigma Tau, Prassis Research Institute, Milan, Italy
3 Laboratory of Environmental Physiology, Granche Blanche Faculty of Medicine, Lyon Cedex, France
4 Department of Physiology, University of Tuebingen, Tuebingen, Germany
5 Chair of Nephrology, Ateneo Viata e Salute, S. Raffaele Hospital, Milan, Italy
* To whom correspondence should be addressed. E-mail: gb.capasso{at}unina2.it.
Hypertension in the Milan strain of rats (MHS) is dependent on primary alteration in renal tubular
sodium reabsorption. The major apical plasma membrane Na+ transporters include the proximal
tubular Na+-H+ exchanger (NHE3), the thick ascending limb Na+-K+-2Cl- co-transport system
(NKCC2), the distal tubular Na+-Cl- co-transporter (NCC) and the collecting duct epithelial sodium
channel (ENaC). The present study explores whether the development of hypertension in the MHS
rats is preceded or paralleled by alterations of mRNA and/or protein levels of these four Na+
transporters. MHS rats were studied at 23-25 days after birth; age-matched Milan normotensive
(MNS) rats were used as controls. GFR, measured by inulin clearance, was significantly (p<0.01)
higher in MHS than in MNS rats, while the mean blood pressure (MBP) was not different in the two
strains of animals indicating that the MHS rats were still in the pre-hypertensive state. NHE3,
NKCC2, NCC and 
-ENaC mRNA abundance was quantified by competitive PCR. In MHS as
compared to MNS, mRNA abundance was unchanged for NHE3 in proximal tubules, higher
(+137±23%)(p<0.005) for NKCC2 in medullary thick ascending limbs of Henle's loops (TAL),
lower (-77±10%)(p<0.005) for NCC in distal convoluted tubules and for -ENaC both in cortical
(-17±3%) (p<0.01) and outer medullary collecting ducts (-31±1%)(p<0.005). Western blot
experiments revealed: 1. unchanged NHE3; 2. a significant increase of NKCC2 in the outer medulla
(+111±14%); 3. a significant decrease of NCC in renal cortex (-57±3%) and of -ENaC both in
renal cortex (-13±3%) and outer medulla (-20±2%), while 
and 
-ENaC remained unchanged.
These data indicate that in the early phase of this model of salt sensitive hypertension there is a
strong up-regulation of NKCC2 along the medullary TAL associated with increased GFR, robust
inhibition of NCC cotransporter along the distal convoluted tubule and modest down-regulation of
-ENaC along the cortical and outer medullary collecting ducts. The interplay of the various Na+
transporters and their different effects on renal sodium handling may well explain why, at this age,
the rats are still in the pre-hypertensive state.
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