Title:TRP Channels as Therapeutic Targets in Kidney Disease and Hypertension
Volume: 13
Issue: 3
Author(s): Paolo Mene, Giorgio Punzo and Nicola Pirozzi
Affiliation:
Keywords:
TRP channels, store-operated Ca2+ channels, receptor-operated Ca2+ channels, hereditary nephrotic syndrome, familial focal glomerulosclerosis, autosomic dominant polycystic kidney disease
Abstract: The Drosophila trp homologue Transient Receptor Potential (TRP) cation channels are ubiquitous in most species
and cell types. The functional TRP subclasses TRPC, TRPV and TRPP gate Ca2+ and other cations in mammalian tissues,
including the kidney. It is now clear that TRP channels play an important role in renal physiology and in certain genetic
disorders of the kidney. Hence, there is considerable interest in targeting mutated or dysfunctional TRP channels in
an effort to treat such diseases. Transcellular epithelial cell Ca2+ reabsorption occurs in the distal tubule via luminal
TRPV5/V6 channels. Indeed, TRPV5 KO mice display phenotypic defects of renal disease, including hypercalciuria and
impaired bone mineral density. Similar to Ca2+, Mg2+ transcellular reabsorption occurs in the distal convoluted tubule via
apical TRPM6/TRPM7 channels. TRPC6 is a component of the glomerular podocyte “slit diaphragm” and its autosomic
dominant mutation has been linked to a familial, steroid-resistant form of nephrotic syndrome. A more common inherited
disorder of the tubular epithelium, autosomal dominant polycystic kidney disease (ADPKD), is at least in part related to
mutation of polycystin 2 (PC2), a protein encoded by the PKD2 gene. PC2 is now identified as TRPP2, a Ca2+-permeable
non-selective cation channel located on the cilia of tubular epithelial cells. TRP-related ion transport may also play a role
in the pathogenesis of arterial systemic and/or pulmonary hypertension through regulation of vascular smooth muscle contraction,
renal perfusion/hemodynamics, as well as the total body balance of divalent cations. Thus, multiple renal TRP
channels are potential targets for pharmacological intervention aimed at preventing or attenuating the burden of chronic
kidney disease.