The Transient Receptor Potential (TRP) superfamily was first described in Drosophila melanogaster and is, based on protein homology, subdivided into several subfamilies – TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPA (ankyrin), TRPML (mucolipin) and TRPN (no mechanoreceptor potential C) (Hall et al., 2019, Montell et al., 2002, Nilius and Owsianik, 2011). Depending on associated proteins, TRP channels are critical in a wide range of physiological processes and appear in many different cell types (Goel et al., 2006, Nilius and Owsianik, 2011, Venkatachalam and Montell, 2007),. The activation mechanisms of TRP channels are diversified and include ligand binding, alterations in temperature, mechanical stress and more (Hall et al., 2019, Khayyat et al., 2020, Nilius and Owsianik, 2011, Venkatachalam and Montell, 2007). The TRPC subfamily accounts seven members of non-selective Ca2+-permeable cation channels that can be, based on their ability to form diverse functional heteromers, clumped into two different groups – namely TRPC3/6/7 and TRPC1/4/5 – TRPC2 being encoded by a pseudogene in humans (Fan et al., 2018, Li, 2017, Staruschenko et al., 2023). The structure of TRPC channels is tetrameric. Each subunit is composed of six transmembrane segments (S1-S6). The Ca2+-permeable cation-pore arises between the two final transmembrane segments (S5-S6) of each monomer and its gating activity can be meticulously regulated (Kaneko and Szallasi, 2014, Montell et al., 2002). Due to such properties, TRPC channels are eligible to function as key molecular players in multiple mechanisms including redox-sensitive, receptor-, and store-operated currents as suggested in non-human experiments (Englisch et al., 2022a, Englisch et al., 2023, Khayyat et al., 2020, Ong et al., 2016, Reiser et al., 2005, Staruschenko et al., 2023, Wang et al., 2008). Diacylglycerol (DAG), for instance, is a prominent physiological activator of TRPC3 and TRPC6 (Fan et al., 2018). In addition, TRPC3 features an uncommonly long third transmembrane segment, that has been suggested to mediate the channel’s mechanosensitivity (Khayyat et al., 2020). In 2002, Riccio et al. analyzed TRPC messenger ribonucleic acid (mRNA) distribution in peripheral tissues and revealed little TRPC5 mRNA but no TRPC3 mRNA in the kidney (Riccio et al., 2002). However, later literature features reports on TRPC channels, including TRPC3 in the kidney (Ilatovskaya and Staruschenko, 2015, Khayyat et al., 2020, Reiser et al., 2005). Unfortunately, most of these studies that we depict below failed to find a consensus on the distribution profiles of the aforementioned channel. Hence, our genuine interest to finally provide such a description not only apprehending rodents, as mostly performed until now, but also extending to human tissue.

The kidney is divided into a renal cortex, an inner and outer medulla that is further subdivided into an inner stripe and outer stripe (Reilly and Ellison, 2000) (Fig. 1). Each nephron – the functional unit of the kidney – is composed of a glomerulus and the corresponding tubular system. The glomerulus is a fenestrated capillary network surrounded by intraglomerular mesangial cells and podocytes that are also referred to as the visceral layer of Bowman’s capsule. The parietal layer represents the peripheral border of Bowman’s space (Khayyat et al., 2020, Shaw et al., 2018). The tubular system is grossly segmented in a proximal convoluted and straight tubule, in an intermediate tubule with a thin descending and ascending leg as well as in a distal straight and convoluted tubule (Reilly and Ellison, 2000) (Fig. 1). However, proximal, and distal tubules will here be distinguished depending on parenchymal localization (cortical/inner or outer stripe) not on morphology (straight/convoluted). While glomeruli are clear to recognize, identification of renal tubules type can be challenging. Proximal tubules are relatively large and feature a nearly lumen filling cuboidal epithelium that is equipped with a prominent brush border (Drenckhahn, 2003). Intermediate tubules, that can be distinguished in both the cortex and medulla, are characterized by a squamous epithelium (Drenckhahn, 2003). In contrast to proximal tubules, distal tubules can be detected in the entire outer medulla. Their epithelium is cuboidal, middle-sized and lacks an apical brush border (Drenckhahn, 2003). Collecting ducts, that do not belong to the nephron, possess a large lumen that is lined with clear definable cuboidal cells including principal and intercalated cells (Drenckhahn, 2003). General renal physiology is detailed elsewhere, since not the focus of this article (Brown et al., 2012, Pluznick, 2013).

Interestingly, TRPC channels are suggested to be critical in both glomerular and tubular physiology and pathophysiology (Englisch et al., 2022a, Hall et al., 2019, Ilatovskaya and Staruschenko, 2015). For instance, Staruschenko et al. recently summarized the involvement of different channels, including TRPC members, in glomerular function, where TRPC3 has been detected in podocytes (Staruschenko et al., 2023). In contrast to TRPC6, little is known about TRPC3 in these cells (Khayyat et al., 2020). It was observed, however, that TRPC3 is upregulated upon TRPC6-knockout in podocytes, suggesting functional redundancy due to similar properties (Kim et al., 2019a, Kim et al., 2018). Besides, TRPC3 expression was increased under pathophysiological conditions such as angiotensin II-mediated hypertension (Eckel et al., 2011, Khayyat et al., 2020). Switching the glomerular cell type – TRPC3 was detected in mesangial cells (Staruschenko et al., 2023). Although TRPC1 and TRPC6 are better investigated in these contractile cells, it is suggested that TRPC3 functions as Ca2+-sensing receptor (CaSR)-operated channel to promote human mesangial cell proliferation (Meng et al., 2014). Combined with its high expression profile in pre-glomerular resistance vessels, it is supposed that TRPC3 is involved in glomerular filtration rate (GFR)- and tubuloglomerular feedback maintenance (Khayyat et al., 2020).

Until now, most of the scientific attention was paid to the glomerular localization and function of TRPC channels. In return TRPC channels belong to the best studied channels in glomeruli (Staruschenko et al., 2023). However, their relevance in the renal tubular system is increasingly investigated which recently motivated us to summarize the current understanding of renal tubular TRPC3 and TRPC6 (Englisch et al., 2022a). Briefly, TRPC6 turned out to be involved in tubular ischemia/reperfusion injuries (Englisch et al., 2022a) and in both oncogenesis and tumor progression of renal cell carcinoma (Englisch et al., 2022a, Kim et al., 2019b, Song et al., 2013). In contrast, TRPC3 was suggested to be involved in luminal osmosensation and vasopressin-induced aquaporin-2 (AQP-2) translocation in the collecting duct (Goel and Schilling, 2010, Goel et al., 2007, Goel et al., 2010). In the proximal tubule TRPC3 is believed to have a nephroprotective function with respect to the sequence of hypercalciuria, nephrocalcinosis, and potentially chronic kidney disease (Awuah Boadi et al., 2021, Ibeh et al., 2019, Shin et al., 2022). A pathogenic role in autosomal dominant polycystic kidney disease (ADPKD) upon TRPP1/2 loss-of-function mutation has also been formulated (Englisch et al., 2022a, Li et al., 2019). However, several open issues remain, since many discrepancies in results of functional investigations exist and convincing microscopical description is still lacking in contrary to TRPC6 (Englisch et al., 2022b).

Due to this, and to the wide relevance of the TRPC3 channel in Ca2+ homeostasis and signaling, there is a need for systematic investigation in mouse and especially human tissue to support and shape the increasing understanding of the involvement of TRPC3 in human kidney – or more specifically tubular – function and dysfunction.