The aim of this study was to investigate whether the effects of aging on oxidative stress markers and expression of major oxidant and antioxidant enzymes associate with impairment of renal function and increases in blood pressure. To explore this, we determined age-associated changes in lipid peroxidation (urinary malondialdehyde), plasma and urinary hydrogen peroxide (H2O2) levels, as well as renal H2O2 production, and the expression of oxidant and antioxidant enzymes in young (13 weeks) and old (52 weeks) male Wistar Kyoto (WKY) rats. Urinary lipid peroxidation levels and H2O2 production by the renal cortex and medulla of old rats were higher than their young counterparts. This was accompanied by overexpression of NADPH oxidase components Nox4 and p22phox in the renal cortex of old rats. Similarly, expression of superoxide dismutase (SOD) isoforms 2 and 3 and catalase were increased in the renal cortex from old rats. Renal function parameters (creatinine clearance and fractional excretion of sodium), diastolic blood pressure and heart rate were not affected by aging, although slight increases in systolic blood pressure were observed during this 52-week period. It is concluded that overexpression of renal Nox4 and p22phox and the increases in renal H2O2 levels in aged WKY does not associate with renal functional impairment or marked increases in blood pressure. It is hypothesized that lack of oxidative stress-associated effects in aged WKY rats may result from increases in antioxidant defenses that counteract the damaging effects of H2O2.

Differences in L-DOPA handling between SHR and WKY cells may result from over-expression of LAT1 and LAT2 transporters in the former. The unique role of Na(+)-dependent transporters (system B(0)) in SHR cells also contributes to the enhanced L-DOPA uptake in these cells.

The protein kinase liver kinase B1 (LKB1) regulates cell polarity and intercellular junction stability. Also, LKB1 controls the activity of salt-inducible kinase 1 (SIK1). The role and relevance of SIK1 and its downstream effectors in linking the LKB1 signals within these processes are partially understood. We hypothesize that SIK1 may link LKB1 signals to the maintenance of epithelial junction stability by regulating E-cadherin expression. Results from our studies using a mouse lung alveolar epithelial (MLE-12) cell line or human renal proximal tubule (HK2) cell line transiently or stably lacking the expression of SIK1 (using SIK1 siRNAs or shRNAs), or with its expression abrogated (sik1(+/+) vs. sik1(-/-) mice), indicate that suppression of SIK1 (∼40%) increases the expression of the transcriptional repressors Snail2 (∼12-fold), Zeb1 (∼100%), Zeb2 (∼50%), and TWIST (∼20-fold) by activating cAMP-response element binding protein. The lack of SIK1 and activation of transcriptional repressors decreases the availability of E-cadherin (mRNA and protein expression by ∼100 and 80%, respectively) and the stability of intercellular junctions in epithelia (decreases in transepithelial resistance). Furthermore, LKB1-mediated increases in E-cadherin expression are impaired in cells where SIK1 has been disabled. We conclude that SIK1 is a key regulator of E-cadherin expression, and thereby contributes to the stability of intercellular junctions.

Several clinical and animal studies suggest that "blood pressure goes with the kidney," that is, a normotensive recipient of a kidney genetically programmed for hypertension will develop hypertension. Intrarenal dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport. The candidate transport systems for L-DOPA, the source for dopamine, include the sodium-dependent systems B(0), B(0,+), and y(+)L, and the sodium-independent systems L (LAT1 and LAT2) and b(0,+). Renal LAT2 is overexpressed in the prehypertensive spontaneously hypertensive rat (SHR), which might contribute to enhanced L-DOPA uptake in the proximal tubule and increased dopamine production, as an attempt to overcome the defect in D1 receptor function. On the other hand, it has been recently reported that impaired arginine transport contributes to low renal nitric oxide bioavailability observed in the SHR renal medulla. Here we review the importance of renal amino acid transporters in the kidney and highlight pathophysiological changes in the expression and regulation of these transporters in essential hypertension. The study of the regulation of renal amino acid transporters may help to define the underlying mechanisms predisposing individuals to an increased risk for development of hypertension.

Rationale:In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-β1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes.Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and Results: SIK1 knockout (sik1 −/−) and wild-type (sik1 +/+ ) mice were challenged to a normal-or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1 −/− mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1 +/+ mice. During high-salt intake, the sik1 +/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1 −/− mice exhibited upregulated transforming growth factor-β1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Bertorello et al SIK1, Hypertension, and Vascular Remodeling 643Elevated arterial blood pressure can occur as a consequence of increased vascular stiffness attributed to both extracellular matrix deposition/remodeling and enhanced contractility/stiffness of VSMCs. [10][11][12][13] Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that mediates extracellular matrix remodeling processes within the vasculature in addition to promote VSMCs differentiation toward a contractile phenotype.14-18 SIK1 participates in a negative feedback mechanism on the TGF-β1 signaling pathway. 19 We have reported that in epithelial cells the loss of SIK1 increased the expression of SNAI2 and TWIST1, known transcription factors involved in fibrosis and extracellular matrix remodeling. Recently, brain SIK1 activity has been shown to be relevant for blood pressure regulation in rodents by regulating sympathetic activity. Higher hypothalamic activity of SIK1 was associated with reduced sympathoexcitatory activity and lower arterial blood pressure in rats after a high-salt diet and intracerebroventricular infusion of Na + . 20Because SIK1 is present in the vasculature and lower SIK1 activity was associated with elevated blood pressure in humans and rodents, we hypothesize that the lack of SIK1 could trigger vascular remodeling processes leading to increased vascular stiffness and consequently to higher blood pressure. Furthermore, these events alone or in combination with other risk factors (high-s...