Renal TRPathies

Abstract

One key function of the kidneys is the ultrafiltration of plasma by glomeruli to dispose of metabolic end products, excess electrolytes, and water. A vast array of ion channels and transporters are critical for filtration, secretion, and resorption of electrolytes to maintain homeostasis. In recent years, investigations have focused on several members of the large transient receptor potential (TRP) family of ion channels, because mutations in genes encoding members of three different TRP ion channel subfamilies have been linked to human kidney diseases. 1 Mutations in PKD1 (encoding TRPP1) and PKD2 (coding for TRPP2) occur at high frequency in individuals with autosomal dominant polycystic kidney disease. 2,3 The latter mutations and the pathophysiology of polycystic kidney disease are not discussed further in this overview because the topic has been covered by numerous insightful review articles. 4 -7 Missense and nonsense mutations in the gene coding for TRPC6 segregate with autosomal dominant FSGS, a kidney disease that leads to progressive renal failure. 8,9 Loss-of-function mutations in TRPM6 are also associated with hypomagnesemia with secondary hypocalcemia (HSH), a rare autosomal recessive disorder. 10 -12 The involvement of TRP channel mutations in hereditary kidney disease has shed new light on the molecular pathogenesis of renal failure and significantly enhanced our appreciation of the physiologic roles of TRP channels on tubular function. In this review, we focus exclusively on TRPC6 and TRPM6. TRPC6 AND PODOCYTE FUNCTIONTRPC6 is a nonselective cation channel and one of the seven members of the classical transient receptor potential (TRPC) family, which can be divided into subfamilies on the basis of amino acid similarity. Whereas TRPC1 and TRPC2 are almost unique, TRPC4 and TRPC5 share approximately 64% amino acid identity. TRPC3, TRPC6, and TRPC7 form a structural and functional subfamily displaying 65 to 78% identity at the amino acid level and share a common activator, diacylglycerol (DAG). 13 DAG is produced by phospholipase C isozymes activated after agonist binding to appropriate receptors, such as the interaction of angiotensin II (AngII) with AT 1 receptors.Like all TRPC family members, TRPC6 harbors an invariant sequence, the TRP box (containing the amino acid sequence EWKFAR), in its C-terminal tail as well as three ankyrin repeats in the N-terminus (Figure 1, A and B). The predicted transmembrane topology is similar to that of other TRP channels with intracellular N-and C-termini, six membrane-spanning helices (S1 through S6), and a presumed pore-forming loop (P) between S5 and S6 (Figure 1, A and B). As deduced from Northern blot analyses, TRPC6 channels are most prominently expressed in lung tissues, 14 where they ABSTRACTMany ion channels and transporters are involved in the filtration, secretion, and resorption of electrolytes by the kidney. In recent years, the superfamily of transient receptor potential (TRP) ion channels have received deserved attention because mutated TRP ch...

Onco-Nephrology

“…Cetuximab has a 10-fold greater affinity for EGFR than natural ligand, making it an effective targeted therapy in these cancers. However, one of the drug's adverse effects is hypomagnesemia (37)(38)(39)(40)(41).…”

“…Magnesium reabsorption in the distal convoluted tubule is, in part, dependent on EGF binding its receptor on the basolateral membrane (37,38,41). Activation of the EGFR sets in motion intracellular signals that stimulate the movement of the cation channel transient receptor potential M6 into the apical membrane, which facilitates the reabsorption of magnesium from the urinary space into the cell (37,38,41).…”

Discrete Control of TRPV4 Channel Function in the Distal Nephron by Protein Kinases A and C

“…Due to activation in response to a broad range of stimuli, including chemical compounds, temperature, mechanical inputs, etc., TRP channels are viewed as essential components in virtually all cellular responses to dynamic environmental changes (1,2). TRP channel dysfunction has been recently linked to a number of hereditary diseases in humans ranging from skeletal dysplasias, neuropathies, and electrolyte imbalance (magnesemia and hypocalcemia) to polycystic kidney disease (3)(4)(5)(6)(7).…”

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

“…TRPM2 has been shown to play an important role in cell proliferation and oxidant-induced cell death in a variety of in vitro settings (15)(16)(17). While several TRP channels are expressed in the kidney and are involved in disease states such as polycystic kidney disease and focal segmental glomerulosclerosis (18,19), the role of TRPM2 in kidney physiology or pathophysiology is unknown.…”