Glomerulonephritis-Induced Changes in Urinary and Kidney MicroRNA Profiles in Rats

Abstract

MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and thus are involved in various physiological and pathological states. Due to their stability in biofluids miRNAs have also been proposed as biomarkers (BMs) for tissue injury. We investigated the usefulness of urinary miRNAs for detection of site-specific renal damage in an antiglomerular basement membrane glomerulonephritis (GN) model in rats by comparing GN-induced urinary miRNAs profiles to traditional and newer protein BMs, and to proximal tubular injury-induced urinary miRNA profiles observed previously after cisplatin (Cp) treatment. Male Wistar Kyoto and Sprague Dawley rats were dosed once with 1, 2.5, and 5 ml/kg nephrotoxic serum (NTS) or 1.5 and 5 ml/kg NTS, respectively. GN and tubular damage were observed histopathologically in all treated rats after 14 days. Although serum creatinine and BUN were not changed, several protein BMs and 74 urinary miRNAs were found to be increased 8 and 14 days after NTS administration. Of these 74 miRNAs, 5 were identified as increased after NTS but not after Cp treatment. Using in situ hybridization two of them, miR-10 b and -100, were found to be localized in distal segments of the nephron, potentially reflecting the tubular injury in those regions. Furthermore, evaluation of both miRNA and mRNA expression in the kidney revealed possible miRNA-mRNA interactions mostly associated with fibrotic and transforming growth factor β signaling. In conclusion, our investigations support the potential of urinary miRNAs as specific BMs for kidney injury, and suggest a role of miRNAs in pathological processes during GN in the kidney.

Mouse population-based evaluation of urinary protein and miRNA biomarker performance associated with cisplatin renal injury

“…5 Similarly, several groups, including ours in collaboration with the HESI Biomarkers of Nephrotoxicity committee, have investigated utility of urinary miRNAs leaked into the urine as adjunct biomarkers that inform site of injury to the renal nephron in conventional Sprague Dawley rats. [6][7][8] Traditional biomarker discovery efforts typically take a reductionist approach, evaluating a set of candidate biomarkers and their differences in abundance between a subset of patients or within constrained model systems. Such systems science approaches seek to discern molecular changes that -for example -distinguish responders from non-responders, suggest disease course or progression, or can inform status of an organ system.…”

“…5 Similarly, several groups, including ours in collaboration with the HESI Biomarkers of Nephrotoxicity committee, have investigated utility of urinary miRNAs leaked into the urine as adjunct biomarkers that inform site of injury to the renal nephron in conventional Sprague Dawley rats. 6–8…”

MicroRNAs and drug-induced kidney injury

“…First, the miR-30 family (miR-30a, -c, and -e) was found to be increased in rat plasma after the administration of contrast agent and these results were validated in a patient cohort where especially miR-30a performed very well in differentiating patients with contrast-induced nephropathy from those without. Even though the number and diversity of miRNA biomarker studies specifically for DIKI are small, the data is promising and results from other kidney diseases including immunoglobulin A nephropathy, ischemic AKI, glomerulonephritis or focal segmental glomerulosclerosis (Ichii, et al, 2014; Pavkovic, Riefke, Frisk, Groticke, & Ellinger-Ziegelbauer, 2015; G. Wang, et al, 2011; J.…”

Effects of a 28-day dietary co-exposure to melamine and cyanuric acid on the levels of serum microRNAs in male and female Fisher 344 rats

“…miRNAs can be released, actively or passively, from cells into blood and other biofluids, and cell-free miRNAs are stable and detectable in biofluids (Etheridge et al , 2011; Schwarzenbach et al , 2014). Because the levels of miRNAs in biofluids may reflect physiological changes and/or specific pathological conditions, including of the kidney, they have the potential to serve as sensitive, minimally invasive biomarkers of toxicity and disease (Aguado-Fraile et al , 2015; Bonventre et al , 2010; Pavkovic et al , 2015). …”