Table 2.
Non-antifibrotic strategies for treating CKD
| Agent | Setting | Primary outcome and/or results |
|---|---|---|
| Vascular calcifcation | ||
| Klotho overexpression | Mice with CKD62 | Enhanced phosphaturia, improved renal function, and decreased calcifcation |
| Exogenous Klotho | Mice with UUO67 and mice with adriamycin-induced CKD67 | Inhibition of renal β-catenin activation, suppression of myofbroblast activation, reduction in extracellular matrix protein expression, and amelioration of renal fbrosis |
| Oxidative stress and NADPH oxidases | ||
| NOX-2 defciency | Mice with STZ-induced diabetic nephropathy74 | No benefcial effect on renal function, and marked increase in NOX-4 at the protein level in the kidney |
| GKT136901* | Leprdb/db diabetic mice80,81 | Reduction in albuminuria and oxidative stress |
| GKT137831* | Diabetic Apoe–/– mice83 | Reduction in ROS production, infammation, vascular complications, and profbrotic markers, such as CTGF, collagen I V, and fbronectin |
| GKT137831* | Ongoing phase I/II study in patients with type 2 diabetes mellitus and diabetic nephropathy84 | GKT137831 was well tolerated |
| NOX-4 defciency | Mice with STZ-induced diabetes,76 mice with UUO,76 and 5/6 nephrectomized mice76 | No benefcial effect on renal function |
| NOX-4 defciency | Mice with UUO85 | Increased tubulointerstitial fbrosis, increased oxidative stress, and decreased antioxidant markers, such as NRf2, at the protein level as well as glutathione S-transferase α at the mRNA level |
| NF-κB | ||
| PDTC | Rats with gentamicin-induced nephropathy,86 5/6 nephrectomized rats,87 and rats with aldosterone and salt-induced CKD88 | Attenuation of renal infammation and renal injury |
| Celastrol | Leprdb/db diabetic mice89 | Reduction in albuminuria and glomerular mesangial matrix along with reduced TGF-β expression at the protein level and collagen IV deposition |
| Energy sensing | ||
| AICAR | High-fat-diet-induced kidney disease in mice102 | Reduction in albuminuria, glomerular mesangial matrix, renal infammation, and lipid accumulation |
| AICAR | OVE26 mice104 | Reduction in albuminuria and renal hypertrophy along with decreased NOX-4 and tumour-suppressor p53 expression at the protein level |
*
Dual NOX-1 and NOX-4 inhibitor.
Abbreviations: AICAR, AMP analogue; ApoE, apolipoprotein E; CKD, chronic kidney disease; CTGF, connective tissue growth factor; NF, nuclear factor; NOX, NADPH oxidase; NRf2, nuclear factor erythroid 2-related factor 2; PDTC, pyrrolidine dithiocarbamate; ROS, reactive oxygen species; STZ, streptozotocin; TGF-β, transforming growth factor β; UUO, unilateral ureteral obstruction.