Na+,K+-ATPase is modulated by angiotensin II in diabetic rat kidney – another reason for diabetic nephropathy?

• Published in: The Journal of physiology Vol. 586; no. 22; pp. 5337 - 5348
• Main Authors: Fekete, Andrea, Rosta, Klara, Wagner, Laszlo, Prokai, Agnes, Degrell, Peter, Ruzicska, Eva, Vegh, Edit, Toth, Miklos, Ronai, Katalin, Rusai, Krisztina, Somogyi, Aniko, Tulassay, Tivadar, Szabo, Attila J, Ver, Agota
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 15-11-2008; Blackwell Publishing Ltd; Blackwell Science Inc
• Subjects: Angiotensin II - pharmacology; Animals; Binding Sites; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - enzymology; Diabetic Nephropathies - etiology; Diabetic Nephropathies - genetics; Kidney - drug effects; Kidney - enzymology; Male; Molecular and Genomic; Phosphorylation; Protein Subunits; Rats; Rats, Wistar; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sodium-Potassium-Exchanging ATPase - chemistry; Sodium-Potassium-Exchanging ATPase - genetics; Sodium-Potassium-Exchanging ATPase - metabolism
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2008.156703

Angiotensin II (ANGII) plays a central role in the enhanced sodium reabsorption in early type 1 diabetes in man and in streptozotocin-induced
(STZ) diabetic rats. This study investigates the effect of untreated STZ-diabetes leading to diabetic nephropathy in combination
with ANGII treatment, on the abundance and localization of the renal Na + ,K + -ATPase (NKA), a major contributor of renal sodium handling. After 7 weeks of STZ-diabetes ( i.v. 65 mg kg −1 ) a subgroup of control (C) and diabetic (D7) Wistar rats were treated with ANGII ( s.c. minipump 33 μg kg −1 h −1 for 24 h; CA and D7A). We measured renal function and mRNA expression, protein level, Serin23 phosphorylation, subcellular
distribution, and enzyme activity of NKA α-1 subunit in the kidney cortex. Diabetes increased serum creatinine and urea nitrogen
levels (C versus D7), as did ANGII (C versus CA, D7 versus D7A). Both diabetes (C versus D7) and ANGII increased NKA α-1 protein level and enzyme activity (C versus CA, D7 versus D7A). Furthermore, the combination led to an additive increase (D7 versus D7A, CA versus D7A). NKA α-1 Ser23 phosphorylation was higher both in D7 and ANGII-treated rats in the non-cytoskeletal fraction, while
no signal was detected in the cytoskeletal fraction. Control kidneys showed NKA α-1 immunopositivity on the basolateral membrane
of proximal tubular cells, while both D7 and ANGII broadened NKA immunopositivity towards the cytoplasm. Our study demonstrates
that diabetes mellitus (DM) increases the mRNA expression, protein level, Ser23 phosphorylation and enzyme activity of renal
NKA, which is further elevated by ANGII. Despite an increase in total NKA quantity in diabetic nephropathy, the redistribution
to the cystosol suggests the Na + pump is no longer functional. ANGII also caused translocation from the basolateral membrane, thus in diabetic states where
ANGII level is acutely elevated, the loss of NKA will be exacerbated. This provides another mechanism by which ANGII blockade
is likely to be protective.