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

Abstract

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.

Aldosterone Antagonists in Monotherapy Are Protective against Streptozotocin-Induced Diabetic Nephropathy in Rats

“…This in line with recent findings of Galuska et al showing that hyperglycemia induces the mislocation of NKA from the basolateral membrane to the cytosol in human tubular cell culture [42]. We also showed that ANGII administration exerts similar changes, while ANGII treatment in STZ-diabetes has a superimposed effect leading to pronounced renal damage and NKA alteration [17]. Here we extended our findings by showing that ACEi and ARB decreases diabetes-induced NKA elevation and prevents enzyme mislocation.…”

Angiotensin II inhibits activity of human organic anion transporter 3 through activation of protein kinase Cα: Accelerating endocytosis of the transporter

“…Another interesting finding from the current study was that although Na/K-ATPase is one of the three components (Na/K-ATPase, Na-dicarboxylate cotransporter and OAT) in the tertiary transport mechanism utilized by hOAT3, and although angiotensin II was previously reported to affect Na/K-ATPase expression (Fekete et al, 2008), Na/K-ATPase seems only to participate in hOAT3 function at the cell surface and does not co-traffic with hOAT3 both in the absence and in the presence of angiotensin II (Fig. 7).…”

“…In addition to hOAT3, angiotensin II has also been shown previously to affect Na/K ATPase expression (Fekete et al, 2008). We therefore asked whether angiotensin II induced hOAT3 internalization is accompanied by Na/K ATPase internalization.…”

Hypoglycemic action of vitamin K1 protects against early-onset diabetic nephropathy in streptozotocin-induced rats

“…In proximal tubules of kidney, Na + is actively reabsorbed by apical Na + -H + exchanger and Na + -HCO 3 -cotransporter and secreted through Na + -K + ATPase [44]. Being the driving force for other secondary Na + transporters, Na + -K + ATPase activity is critical and tightly controlled in renal cells.…”