TRP Channels as Therapeutic Targets in Kidney Disease and Hypertension

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 Ca(2+)-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.