**3. Hormonal actions and interactions for regulating sodium reabsorption in PTCs**

Sodium reabsorption from glomerular filtrates is an important function of PTCs in the maintenance of systemic hemodynamics. Impairment of this function is associated with the abnormal regulation of blood pressure, especially in patients with CKD. Moreover, increased PTC sodium reabsorption causes glomerular hyperfiltration via the tubuloglomerular feedback mechanism, particularly in diabetes (Thomson, Vallon, and Blantz 2004).

Angiotensin II and insulin are two major hormones involved in regulating the expression and function of megalin (Hosojima et al. 2009) (Fig. 2), but no hormones have been

Angiotensin II downregulates the expression and function of megalin via the extracellularsignal-regulated kinase (ERK)1/2 signaling pathway in cultured PTCs (Hosojima et al. 2009). Intrarenal levels of angiotensin II are augmented in CKD (Kobori et al. 2007), which is involved in the development of hypertension as discussed below. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are thus likely to target the increased action of angiotensin II in the kidney. These agents may be effective in suppressing the reduced expression of megalin in CKD and in preventing proteinuria/albuminuria (Tojo et

Megalin also appears to regulate the intrarenal actions of angiotensin II by internalizing angiotensin II (Gonzalez-Villalobos et al. 2005) and angiotensin-(1-7) (Gonzalez-Villalobos et al. 2006), as well as mediating the endocytosis of angiotensinogen that is filtered by

Insulin is involved in the upregulation of megalin, which in turn may be associated with increased endocytosis and metabolism of glomerular-filtered proteins, leading to intracellular metabolic overload. Cross-talk between insulin-insulin receptor substrate/phosphoinositide 3-kinase and angiotensin II-ERK1/2 signaling pathways was previously observed in cultured PTCs (Hosojima et al. 2009), and the balance between the actions and interactions of angiotensin II and insulin may also be important in regulating the expression of megalin *in vivo*. Hyperinsulinemia associated with metabolic syndrome is thought to stimulate insulin signaling in PTCs, while impaired insulin signaling (so-called insulin resistance) is suggested to occur in kidney cells in type 2 diabetic models; moreover, the intrarenal activation of angiotensin II appears to be associated with the development of insulin resistance (Tiwari et al. 2007). Recently, megalin was shown to be downregulated by the lipopolysaccharide-tumor necrosis factorα-ERK1/2 signaling pathway that may also impair insulin signaling in diabetes (Takeyama et al. 2011). In addition, positive control of megalin expression has been demonstrated by peroxisome proliferator-activated receptor isoforms peroxisome proliferator-activated receptor (PPAR)α and PPARγ and their insulin-sensitizing agonists

**3. Hormonal actions and interactions for regulating sodium reabsorption in** 

Sodium reabsorption from glomerular filtrates is an important function of PTCs in the maintenance of systemic hemodynamics. Impairment of this function is associated with the abnormal regulation of blood pressure, especially in patients with CKD. Moreover, increased PTC sodium reabsorption causes glomerular hyperfiltration via the tubuloglomerular feedback mechanism, particularly in diabetes (Thomson, Vallon, and

**2.2 Hormones regulating the expression and function of endocytic receptors** 

identified that regulate cubilin and amnionless expression.

**2.2.1 Angiotensin II** 

glomeruli (Pohl et al. 2010).

al. 2003).

**2.2.2 Insulin** 

(Cabezas et al. 2011).

**PTCs** 

Blantz 2004).

#### **3.1 Major transporters involved in sodium reabsorption and regulated by hormones in PTCs**

Various transporters and channels are involved in sodium reabsorption in the apical and basolateral membranes of PTCs. Here, we focus on three types of apical transporters (Fig. 2).
