A broad objective in systems biology is to identify every gene expressed in every cell type in the body.  In kidney, we have used RNA-seq and protein mass spectrometry in microdissected kidney tubule segments to map expression of all genes in all renal tubular epithelia.  Because collecting ducts (CDs) contain a mixture of principal cells (PCs) and intercalated cells (ICs), we have resolved separate transcriptomes in these cell types using single-cell RNA-seq. Data have been provided to the kidney research community through web-based sharing of curated data sets (https://esbl.nhlbi.nih.gov/Databases/KSBP2/). These data sets can be browsed, searched or downloaded, allowing them to be ‘mined’ to tie gene expression patterns to physiological functions of different renal epithelial cells. 

Because signaling through GPCRs is vital to control of transport and metabolism in the kidney, we have used the data to curate all GPCRs present in mammalian genomes amounting to 790 genes (https://esbl.nhlbi.nih.gov/Databases/GPCRs/) and mapped them to each of 14 renal tubule segments  and to PCs and ICs of the CD (https://esbl.nhlbi.nih.gov/Databases/GPCRs/TubuleTPM.html).  One area of interest is regulation of aquaporin-2 (AQP2) in principal cells. Although it is well known that regulation of AQP2 trafficking and transcription are dependent on increased cAMP secondary to the G_as-coupled vasopressin V2 receptor (Avpr2), two other G_as-coupled receptors were identified in PCs. These are the prostaglandin EP4 receptor (Ptger4) and the calcitonin-related receptor-like receptor (Calcrl), which binds adrenomedullin in collecting duct PCs. Ligand interactions with both receptors have been shown to increase cAMP and water permeability in collecting ducts, pointing to alternative treatment modalities in X-linked nephrogenic diabetes insipidus due to mutations in Avpr2. In addition, some G_αs-coupled receptors expressed in collecting duct are intercalated-cell-specific (namely, the secretin receptor [Sctr] and β adrenergic receptors [Adrb1 and Adrb2]), which have been shown to regulate acid-base transport.  In addition to the vasopressin V2 receptor, another vasopressin receptor is also expressed in the collecting duct (viz. the V1a receptor), and is found only in intercalated cells. 

Aside from the renal collecting duct, the epithelial cells of the nephron, including the subsegments of the proximal tubule, the thin and thick limbs of Henle’s loop, macula densa and distal convoluted tubule all have been found to express combinations of GPCRs that are indicative of intricate regulation of transport and metabolism (Poll et al. Am J Physiol 2021; 321: F50-F68), much of which remains to be investigated.