MicroRNAs as markers to monitor endothelin‐1 signalling and potential treatment in renal disease: Carcinoma − proteinuric damage − toxicity

This review highlights new developments in miRNA as diagnostic and surveillance tools in diseases damaging the renal proximal tubule mediated by endothelin in the field of renal carcinoma, proteinuric kidney disease and tubulotoxicity. A new mechanism in the miRNA regulation of proteins leads to the binding of the miRNA directly to the DNA with premature transcriptional termination and hence the formation of truncated protein isoforms (Mxi2, Vim3). These isoforms are mediated through miRNA15a or miRNA 498, respectively. ET‐1 can activate a cytoplasmic complex consisting of NF‐κB p65, MAPK p38α, and PKCα. Consequently, PKCα does not transmigrate into the nucleus, which leads to the loss of suppression of a primiRNA15a, maturation of this miRNA in the cytoplasm, tubular secretion and detectability in the urine. This mechanism has been shown in renal cell carcinoma and in proteinuric disease as a biomarker for the activation of the signalling pathway. Similarly, ET‐1 induced miRNA 498 transmigrates into the nucleus to form the truncated protein Vim3, which is a biomarker for the benign renal cell tumour, oncocytoma. In tubulotoxicity, ET‐1 induced miRNa133a down‐regulating multiple‐drug‐resistant related protein‐2, relevant for proteinuric and cisplatin/cyclosporine A toxicity. Current advantages and limitations of miRNAs as urinary biomarkers are discussed. Review: This review highlights the use of miRNAs as urinary markers for proximal tubular damage via proteinuria, and in renal cancer (miRNA15a) and in nephrotoxicity (miRNA 133a). All three conditions exert their effect by endothelin‐1 stimulation leading to a specific signalling cascade. In nephrotoxicity, the classical protein repression of an ATP‐binding cassette (ABC) transporter, the multidrug resistance associated protein 2 (MRP2), through miRNA133a leads to tubular damage by retention of CyA and Cisplatin. In proteinuria and in renal cancer, protein kinase C α is down‐regulated and no longer able to suppress miRNA15a maturation. This is achieved by a novel mechanism: miRNA re‐entering the nucleus, binding directly to DNA. This leads to premature transcriptional termination, forming the truncated gene, Mxi‐2, which further accelerates miRNA 15a maturation. Meanwhile, the activation of NF‐κB is ongoing unrestrictedly.