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MOLECULAR AND GENOMIC |
1 1st Department of Pediatrics, Semmelweis University Budapest, H-1082, Budapest, Hungary
2
Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, H-1088, Budapest, Hungary
3
2nd Department of Medicine and Nephrology, University of Pecs, Faculty of Medicine, H-7624, Pecs, Hungary
4
2nd Department of Medicine, Semmelweis University, Budapest, H-1082, Budapest, Hungary
5
Gottsegen National Institute of Cardiology, H-1096, Budapest, Hungary
6
Research Group for Pediatrics and Nephrology of the Hungarian Academy of Sciences and of the Semmelweis University Budapest, H-1082, Budapest, Hungary
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 
-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 -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 -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 -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.
(Received 11 May 2008;
accepted after revision 23 September 2008;
first published online 25 September 2008)
Corresponding author A. Ver: Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, Budapest, Hungary H-1444. Email: veragota{at}puskin.sote.hu
Related Article
J. Physiol. 2008 586: 5283.
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  P. Rossing Is renal Na+,K+-ATPase a new target for renin-angiotensin blocking agents in diabetic nephropathy? J. Physiol., November 15, 2008; 586(22): 5283 - 5283. [Full Text] [PDF]
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