PerspectiveTherapy

TRP'ing up chronic kidney disease

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Science  08 Dec 2017:
Vol. 358, Issue 6368, pp. 1256-1257
DOI: 10.1126/science.aar3572

Chronic kidney disease (CKD) describes a permanent and considerable loss of kidney function, which affects approximately 1 in 10 people worldwide (1). It is associated with increased risk of end-stage renal disease (ESRD), a condition that requires kidney transplantation or dialysis. Because the major causes of CKD are obesity, hypertension, and diabetes, the population at risk continues to grow (2). New therapies that can prevent or slow progression of disease are desperately needed. On page 1332 of this issue, Zhou et al. (3) show that pharmacological inhibition of a calcium channel, transient receptor potential canonical-5 (TRPC5), can delay progression of kidney disease due to hypertension.

Over the past 15 years, two findings have helped to drive a better understanding of CKD. The first is the realization that podocytes, one of the cell types that comprise the blood filtration barrier in the kidney, are nondividing cells that cannot be renewed once lost (4). Although the exact mechanism is unclear, many forms of progressive kidney disease are associated with reduced podocyte numbers (5). Thus, preventing injury and reducing podocyte loss will be essential to any therapy. The second is that genetic susceptibility can play an important role in CKD progression (6). More than 25 genes that contribute to CKD development have been identified. Although this list continues to grow, there is increasing consensus from these genetic analyses that podocyte injury induces actin cytoskeletal changes via activation of the small GTP-binding protein (G protein) RAC1 that leads to elevation of cytoplasmic Ca2+ and subsequently podocyte death or detachment into the urine (7). A rational approach to drug development might involve inhibiting this pathway to preserve podocyte function.

TRPC5 in podocyte injury and loss

TRPC5 translocation to podocyte membranes induces loss through cytoskeletal changes and thereby compromises the filtration barrier in CKD.

GRAPHIC: K. SUTLIFF/SCIENCE

The TRPC channels are a subgroup of the larger TRP superfamily of Ca2+-permeable nonselective cation channels. In the kidney, TRPC channels are regulated by binding of the hormone angiotensin II (AngII) to the angiotensin receptors (8). Angiotensin receptors are the major target of drugs used to control hypertension. Previously, a gain-of-function mutation of TRPC6 was genetically linked to a familial form of CKD called focal segmental glomerulosclerosis (FSGS) that is caused by increased podocyte loss (9). The related channel, TRPC5, is implicated in the pathogenesis of FSGS as mice lacking TRPC5 are protected from some forms of kidney injury (10) and because it is translocated to the cell surface after RAC1 activation (11) (see the figure). This suggested that targeting TRPC5 might be relevant for injured podocytes.

Zhou et al. tested this hypothesis using a rat model of CKD in which the human angiotensin type 1 receptor (AT1R) is specifically overexpressed in podocytes. These rats over-respond to AngII and develop substantial leakage of serum proteins into the urine (proteinuria, an indication of compromised filtration by the kidney) that is not due to systemic hypertension because AT1R is only expressed on podocytes. They found that podocytes in these mice had increased Ca2+ channel activity that is due to TRPC5 and not TRPC6. AT1R-induced Ca2+ channel activity was elevated in podocytes at the onset of AngII-induced podocyte injury and further increased as disease progressed. To test whether inhibition of TRPC5 in animals could ameliorate disease, a small-molecule inhibitor of TRPC channels, ML204, was administered. Given at the onset of disease, ML204 prevented AT1R-induced injury of the kidney filtration barrier as evidenced by reduced proteinuria. More important, administration of ML204 at a later time point could arrest the progression of kidney injury.

ML204 is not specific to TRPC5 but also blocks TRPC4 and TRPC6. The authors identified a new compound, AC1903, that displays higher specificity toward TRPC5. AC1903 was able to prevent disease progression in the AT1R rat model. Importantly, AC1903 halted disease progression in a more physiological model of kidney injury, the Dahl salt-sensitive rat, a well-established model of hypertensive kidney disease. Administration of AC1903 to these rats attenuated podocyte loss when given either before or after the onset of disease.

The exact function of TRPC5 inhibition in controlling CKD progression is unclear. Zhou et al. showed that AT1R signaling induces the production of reactive oxygen species (ROS) and reduces cell viability. Both ROS and cell death were attenuated by inhibition of TRPC5. However, as TRPC6 and TRPC5, as well as AT1R, are expressed in a wide variety of cell types, it cannot be ruled out that TRPC5 inhibition mediates its effects on CKD through other cells. It was recently suggested that TRPC5 is not involved in CKD as podocyte-specific overexpression of TRPC5 in mice did not disrupt the filtration barrier nor did it aggravate injury induced by the innate signaling molecule, bacterial lipopolysaccharide (12). Given that TRPC5 is sequestered in intracellular vesicles and translocated to the cell surface after RAC1 activation (11), it is unclear whether the overexpressed TRPC5 is localized to the cell surface.

The study by Zhou et al. is exciting as it suggests that data generated over the last decade can, at last, be used as the basis for the rational development of drugs that prevent or arrest the progression of CKD. Whether ML204 and AC1903 will be the basis of a new class of therapeutics, however, remains to be determined. Both drugs have relatively poor affinities for their targets and have very short half-lives in the animals. Although the authors report little toxicity of AC1903 in rats, side effects may have been masked by the very short half-life of the molecule and the relatively short period of treatment. Given the behavioral abnormalities seen in mice lacking TRPC5 (13), it may be important to limit exposure of TRPC5 inhibitors to the brain. Regardless of whether TRPC5 inhibitors make it into the clinic, the study of Zhou et al. marks an important step forward in the search for targeted therapies for this unmet medical need.

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