Table 1.
Non-RAAS Antiproteinuric Therapies: Major Recognized and Proposed Mechanisms
| Agent | Primary Activity | Proposed Antiproteinuric Target |
Major Proposed Mechanism |
|---|---|---|---|
| Glucocorticoids | Immunosuppressant | Podocyte | Transcriptional or translational regulator of nephrin and other podocyte proteins |
| ACTH | Immunosuppressant | Systemic | Increase in endogenous steroids |
| Podocyte | Melanocortin receptor agonist | ||
| Calcineurin inhibitor | Immunosuppressant | Podocyte | Arterial vasoconstriction leading to decreased albumin delivery; transcriptional or translational regulator of TRPC6; blockade of synaptopodin dephosphorylation |
| Mycophenolate | Immunosuppressant | Unknown | No specific mechanism identified |
| Rituximab | Immunosuppressant | Podocyte | Restoration of sphingomyelinase signaling |
| Omega-3 fatty acids | Anti-inflammatory, lipid-lowering |
Podocyte | Transcriptional or translational regulator of nephrin and other podocyte proteins; reduction of profibrotic and proinflammatory molecules |
| Mesangial cell | Reduces mesangial cell proliferation | ||
| TNF antagonism | Anti-inflammatory | Podocyte | Transcriptional regulation of nephrin, paxillin, focal adhesion kinase; preservation of cytoskeleton rearrangement with additional unclear mechanism; regulation of MAP kinase |
| Mesangial cell | Anti-inflammatory | ||
| TGF-β antagonism | Antifibrotic, cytoprotective | Podocyte | Antiapoptotic |
| Retinoids | Cell differentiation Apoptosis Anti-inflammatory Antiproliferative |
Podocyte | Transcriptional regulator of nephrin, synaptopodin, podocin, WT1; inhibition of cell differentiation and proliferation, anti-inflammatory |
| Statins | Lipid metabolism | Podocyte | Antiapoptotic, anti-inflammatory, antioxidant |
| Mesangial cell | Antiproliferative | ||
| Nondihydropyridine calcium channel blockers |
Hemodynamic | Glomerular capillaries | Glomerular capillary pressure reduction |
| Thiazolidinediones | Antiglycemic/metabolic | Podocyte | Transcriptional regulator of nephrin; anti-inflammatory, antifibrotic |
| Glomerular cell | Preservation of permeability regulation | ||
| Vitamin D | Anti-inflammatory | Podocyte | Transcriptional regulator of nephrin, podocin; blockade of Wnt/beta- catenin signaling; activation of PI-3-kinase/AKT |
| Pentoxifylline | Cytokine antagonism | Unknown | Unknown |
| Pirfenidone | Antifibrotic | Mesangial cell | Antifibrotic |
| Unknown | RNA processing; antioxidant | ||
| Tranilast | Antifibrotic | Fibroblasts | Antifibrotic |
| Mesangial cell | Antiproliferative | ||
| Triptolides | Immunosuppressant | Podocyte | Antioxidant; regulation of MAP kinase activation |
| Antiplatelet drugs | Anticoagulant | Glomerular arterioles | Regulation of renal blood |
| Glomerular capillaries | Suppression of platelet coagulation, adhesion; preservation of permeability, unclear mechanism |
||
| Mesangial cell | Antiproliferative | ||
| Unknown | Antioxidant | ||
| Erythropoietin | Erythropoiesis | Podocyte | Antiapoptotic; transcriptional regulator of nephrin and other podocyte proteins |
| VEGF | Angiogenesis | Podocyte | Transcriptional or translational regulator of nephrin |
| Endothelial cell | Regulator of vasodilation and permeability | ||
| AGE antagonism | Product of nonenzymatic glycoxidation from diabetes |
Podocyte | Transcriptional or translational regulator of nephrin; anti- inflammatory, antioxidant, antifibrotic, VEGF suppression |
| Endothelin antagonist | Vasoconstriction | Unknown | Regulation of renal blood flow; anti-inflammatory, antifibrotic |
| Antioxidants (Nrf2, bardoxolone) | Antioxidant | Unknown | Antioxidant, anti-inflammatory |
| Ruboxistaurin | Protein kinase-C inhibition | Unknown | Antifibrotic unknown |
| PDGF antagonism | Angiogenesis | Unknown | Antifibrotic |
| Sulodexide | Anticoagulant, antithrombotic | Endothelial cell | Preservation of endothelial layer |
| Diet | Low protein | Unknown | Unknown and no clear evidence |
| Plant proteins | Mesangial cell | Antiproliferative | |
| Unknown | Antiproliferative, antioxidant | ||
| Weight loss | NA | Glomerular cell | Decreasing glomerular hyperfiltration, antioxidant, antiapoptotic, anti- inflammatory |
Abbreviations: RAAS, renin–angiotensin–aldosterone system; ACTH, adrenocorticotropic hormone; TRPC6, transient receptor potential C6; TNF, tumor necrosis factor; MAP, mean arterial pressure; TGF-β, transforming growth factor-beta; WT1, Wilms tumor-1; Pl-3, phosphatidylinositol-3-kinase; VEGF, vascular endothelial growth factor protein; AGE, advanced glycation end product; Nrf2, nuclear factor erythroid-related factor 2; NA, not applicable.