**3.2.5 Aldosterone**

310 Basic and Clinical Endocrinology Up-to-Date

and local tissue paracrine mechanisms. However, more recently it was also shown to

Insulin is an important hormone that regulates sodium uptake as well as glucose metabolism in PTCs. In patients with metabolic syndrome, serum levels of insulin are elevated by a mechanism of insulin resistance in the liver and skeletal muscles. Increased levels of insulin are likely to augment sodium uptake in PTCs (Baum 1987) as well as other nephron segments such as thick ascending limbs (Mandon et al. 1993) and collecting ducts (Takahashi, Ito, and Abe 1996), causing extracellular fluid expansion and hypertension. Insulin has been shown to acutely and chronically stimulate the function of NHE3 in cultured PTCs (Fuster et al. 2007), and its infusion is associated with increased blood

Diabetic kidneys, however, have been demonstrated to have impaired expression of renal insulin receptors (Tiwari et al. 2007). In kidney-specific insulin receptor KO mice, basal systolic blood pressure was increased and natriuresis was reduced in response to a volume load (Tiwari et al. 2008). The greatest relative reduction of the insulin receptor in these mice was found in the thick ascending limb and collecting duct, and renal production of NO was likely to be reduced. A previously uncharacterized role of the insulin receptor in these nephron segments may thus be associated with sodium and water reabsorption via NO

Glucocorticoids, whether endogenous, as in Cushing syndrome, or exogenous, via pharmacologic provision, induce hypertension (Mangos et al. 2003). They directly stimulate NHE3 through both acute and chronic mechanisms (Bobulescu and Moe 2009). The acute effect of glucocorticoids on cell surface NHE3 is mediated by the activation of HNE3 exocytosis (Bobulescu et al. 2005) and a glucocorticoid receptor-dependent mechanism that activates serum and glucocorticoid-inducible kinase1 (SGK1) in a nongenomic manner (Wang et al. 2007). Glucocorticoids have also been found to enhance the function of insulin

Glucagon-like peptide 1 (GLP1) receptors are expressed in pancreatic cells and other cells such as PTCs (Schlatter et al. 2007). Administration of recombinant GLP1 to Dahl saltsensitive rats resulted in an antihypertensive effect, due mainly to its diuretic and natriuretic actions (Yu et al. 2003). GLP1 was also found to induce natriuresis in healthy subjects and insulin-resistant obese men through its action on PTCs (Gutzwiller et al. 2004). Hyperglomerular filtration in obese men was improved following this treatment, which was

GLP1 receptor agonistic agents have been used in the treatment of hyperglycemia by acting on GLP1 receptors in pancreatic ß-cells to stimulate insulin synthesis. The GLP1 receptor agonist exendin-4 also decreases sodium reabsorption in PTCs by affecting NHE3 activity (Carraro-Lacroix, Malnic, and Girardi 2009) and reduces blood pressure in a salt-sensitive hypertension mice model (Hirata et al. 2009). Such agents are also suggested to be clinically

function in an autocrine or intracrine manner (Li et al. 2011).

pressure in rats (Brands et al. 1991) and humans (Gans et al. 1991).

**3.2.2 Insulin** 

production.

**3.2.3 Glucocorticoids** 

in stimulating NHE3 activity (Klisic et al. 2002).

likely to be mediated by tubuloglomerular feedback mechanisms.

relevant in reducing blood pressure (Vilsboll et al. 2007; Klonoff et al. 2008).

**3.2.4 Glucagon-like peptide 1** 

Aldosterone stimulates the activity and surface expression of NHE3 in human primary PTCs, which is inhibited by the mineralocorticoid receptor blocker spironolactone and by the epidermal growth factor receptor (EGFR)-kinase inhibitor (Drumm et al. 2006). Aldosterone was found to regulate NHE3 by a nongenomic mechanism (Good, George, and Watts 2006). Aldosterone/mineralocorticoid receptor stimulation is also known to affect PTCs by inducing cellular senescence (Fan et al. 2011), suggesting that it is a potential therapeutic target in CKD.
