Somatostatin in renal physiology and autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, leading to growth in kidney volume and renal function decline. Although therapies have emerged, there is still an important unmet need for slowing the rate of disease progression in ADPKD. High intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) are involved in cell proliferation and fluid secretion, resulting in cyst formation. Somatostatin (SST), a hormone that is involved in many cell processes, has the ability to inhibit intracellular cAMP production. However, SST itself has limited therapeutic potential since it is rapidly eliminated in vivo. Therefore analogues have been synthesized, which have a longer half-life and may be promising agents in the treatment of ADPKD. This review provides an overview of the complex physiological effects of SST, in particular renal, and the potential therapeutic role of SST analogues in ADPKD.

Keywords: ADPKD; cAMP; renal physiology; somatostatin; somatostatin analogues.

FIGURE 1

SST: its precursors and cleavage products (modified from Patel et al. [13]).

FIGURE 2

Schematic representation of the pathophysiological processes that drive cyst formation and growth in renal tubular epithelial cells of the collecting duct in ADPKD and the mechanism of action of vasopressin V2 receptor antagonists and SST analogues. In ADPKD, the polycystin complex (formed by the proteins PC1 and PC2 on the apical membrane) is dysfunctional, which leads to diminished calcium influx or diminished release of calcium from intracellular stores. Low intracellular calcium levels in turn stimulate activation of adenylate cyclase (AC), which converts adenosine triphosphate into cAMP. cAMP is an important player in several pathways that could possibly lead to cyst expansion. cAMP increases cell proliferation via protein kinase A and activation of the Ras/Raf/ERK pathway. Furthermore, cAMP activates apical-positioned chloride channels (CFTR channels), leading to fluid secretion into the cyst lumen. cAMP production can be inhibited by blocking the vasopressin V2 receptor (V2R), which is coupled to G stimulatory (Gs) proteins that can activate AC. Activation of the SST receptor (SSTR) can inhibit cAMP production in a direct and indirect way. AC can be directly inhibited by the receptor-coupled G inhibitory (Gi) proteins. Activation of these Gi proteins can also activate calcium channels and stimulate intracellular release of calcium via phospholipase C, which can restore intracellular calcium stores. This leads indirectly to inhibition of cAMP production. Orange and grey lines indicate that the pathway is activated or inactivated, respectively.

FIGURE 3

Effect of the SST analogue lanreotide 120 mg subcutaneously once every 4 weeks compared with control treatment in a 2.5-year prospective trial in patients with ADPKD. (A) The change in eGFR 16 weeks after the last dose of lanreotide (measured at a post-treatment visit) compared with the baseline pre-treatment value [lanreotide −3.58 versus control −3.45, difference −0.13 (95% CI −1.76–1.50) mL/min/1.73 m²/year, P = 0.88]. (B) The change in height-adjusted TKV (hTKV) measured at the same time points [lanreotide 4.15 versus control 5.56, difference −1.33%/year (95% CI −2.41 to −0.24), P = 0.02]. Boxplots show predicted mean and 25 and 75th percentiles and the lower and upper ends of the error bars show predicted 2.5 and 97.5th percentiles, respectively, as derived from mixed model analyses (from reference Meijer et al., JAMA in press).