Late intervention in the remnant kidney model attenuates proteinuria but not glomerular filtration rate decline

Abstract

Aim The use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting. Methods We used the remnant kidney (subtotal nephrectomy [SNX]) rat model that develops a decline in GFR in conjunction with heavy proteinuria and hypertension along with the histological hallmarks of CKD in humans, glomerulosclerosis and tubulointerstitial fibrosis. Using agents that had been shown to improve GFR as well as proteinuria in the prevention setting, angiotensin‐converting enzyme (ACE) inhibition with enalapril and SIRT1 activation with SRT3025, treatment was initiated 6 weeks after SNX. Results While enalapril reduced blood pressure, proteinuria and histological injury, it did not improve GFR, as measured by inulin clearance. SRT3025 improved neither GFR nor structural damage despite a reduction in proteinuria. Conclusion These findings demonstrate that neither a reduction in proteinuria nor a reversal of structural damage in the kidney will necessarily translate to a restoration of kidney function.

Comprehensive analyses of the microRNA–messenger RNA–transcription factor regulatory network in mouse and human renal fibrosis

“…Enalapril may exert antifibrotic effects on a variety of fibrosis tissues, such as peritoneal fibrosis ( Lee et al, 2011 ), pathological cardiac hypertrophy and fibrosis ( Kushwaha et al, 2012 ; Ham et al, 2018 ), liver fibrosis ( Kushwaha et al, 2012 ), and kidney fibrosis ( Kushwaha et al, 2012 ; Molnar et al, 2018 ), even if the short-term use of enalapril confers long-term protection against target organ damage ( Hale et al, 2012 ), or delayed intervention with enalapril had parallel effects on tubulointerstitial, vascular damage, and glomerulosclerosis, with regression of existing lesions ( Adamczak et al, 2003 ). Enalapril significantly alleviates mesangial matrix expansion, interstitial collagen IV deposition, and renal fibrosis ( Ougaard et al, 2018 ; Greite et al, 2020 ; Veitch et al, 2021 ). Enalapril also attenuated renal fibrosis in UUO rats by suppressing apoptosis of renal tubular epithelial cells ( Yang et al, 2019 ) or regulating fibroblast activation (ɑ-SMA), pro-inflammatory cytokine TGF-β, mast cell infiltration, and, probably, mast cell degranulation ( Sun et al, 2016 ).…”

Comprehensive bibliometric analysis of sirtuins: Focus on sirt1 and kidney disease

“…In vivo and in vitro evidence shows that Sirt1 can serve as an important potential pharmacological target in kidney disease ( Figure 8 ). Several drugs available in kidney disease have also been shown to be partially contribute to the activation of the sirt1, such as sodium glucose co-transporter two inhibitors ( Packer, 2020 ), angiotensin-converting enzyme inhibitor (enalapril) ( Veitch et al, 2021 ), angiotensin Ⅱ receptor blocker (olmesartan) ( Gu et al, 2016 ), and statins ( Khayatan et al, 2022 ). In addition, some small molecule compounds, especially some natural compounds, targeting sirt1 may also serve as potentially promising candidates for the treatment of kidney diseases, like RSV, Catalpol and Astragaloside IV.…”