Dysregulation of renal salt and water transport proteins in diabetic Zucker rats.
BACKGROUND
Diabetic nephropathy is commonly associated with renal salt and water retention and hypertension. The molecular mechanisms involved and how the kidney responds to this volume expansion, in terms of renal transporter regulation, are not understood.


METHODS
Targeted proteomics employing semiquantitative immunoblotting were used to investigate regulation of abundance of the primary salt and water transport proteins of the kidney, in 6-month-old lean and obese Zucker rats, a model for Type II diabetes.


RESULTS
Obese rats were significantly heavier, had larger kidneys, increased plasma creatinine and glucose levels and elevated blood pressures. Furthermore, they had a marked decrease in abundance of many pre-macula densa renal sodium transporters. Mean band densities (% lean) were: in cortex, sodium phosphate cotransporter (NaPi-2), 68%, and sodium hydrogen exchanger (NHE3), 66%; and in outer medulla, NHE3, 39%, and the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), 37%. Collecting duct proteins also were markedly reduced. In inner medulla, aquaporins-2, -3, and -4 were reduced to, 46, 48, and 46%, respectively, and the apical urea transporter, UTA1 to 52%. In contrast, post-macula densa sodium transporters were less affected. The thiazide-sensitive Na-Cl cotransporter (NCC) was 106% and the alpha- beta- and gamma-subunits of the epithelial sodium channel (ENaC), 54, 121, and 84% of lean, respectively.


CONCLUSIONS
In obese rats, selective decreases for pre-macula densa sodium transporters may reflect decreased glomerular filtration rate and glomerulotubular balance. This potentially could reduce blood pressure by decreasing proximal tubule sodium reabsorption.
Bickel
Crystal A
CA
Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington DC 20007, USA.
Knepper
Mark A
MA
Verbalis
Joseph G
JG
Ecelbarger
Carolyn A
CA
D000818:Animals; D001794:Blood Pressure; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D008138:Loop of Henle / Q000378:metabolism; D008297:Male; D009765:Obesity; D051381:Rats; D011924:Rats, Zucker; D012964:Sodium / Q000378:metabolism; D012965:Sodium Chloride / Q000378:metabolism*; D014867:Water / Q000378:metabolism*
D002352:Carrier Proteins; D014867:Water; D012965:Sodium Chloride; D012964:Sodium; D003404:Creatinine