Hederagenin: Molecular Mechanisms and Therapeutic Potential for Chronic Kidney Disease

TO THE EDITOR Chronic kidney disease (CKD) is a leading public health concern that affects 15%-20% of the adult population globally.[1] Although angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers showed the beneficial effects in CKD patients, most of CKD patients inevitably progress to end-stage renal disease and need replacement therapies such as renal dialysis and transplantation.[1] However, renal dialysis and transplantation are costly and not curative.[2,3] Mounting publications have highlighted that natural products were demonstrated to be as an important source of new drugs over the 40 years.[4] Accumulated evidence has suggested that natural products have long been used as a promising therapeutic strategy for the prevention and treatment of CKD.[5] Hederagenin, a pentacyclic triterpenoid, is widely distributed in a variety of edible and medicinal plants, such as English ivy, Fructus Akebiae and Cyclocarya paliurus.[6] Hederagenin displays various biological effects, such as anti-tumor and anti-inflammatory activities.[6] Janus kinase/signal transduction and transcription activation (JAK/STAT) pathway is regulated by many cytokines and growth factors in various diseases.[7] Recently, Zhong et al.[7] published findings in the Integrative Medicine in Nephrology and Andrology indicating that hederagenin improves renal function and glomerular injury by inhibiting JAK/STAT pathway in adriamycin-induced nephropathy. This study highlights therapeutic potential of hederagenin as a therapeutic agent for nephrotic syndrome, which is a condition characterized by podocyte injury and subsequent glomerulosclerosis, mirroring pathological features of non-immune primary glomerulonephritis.[8] Increasing evidence has shown that natural products are extensively used to treat diseases related to glomerular damage.[7,9] Zhong et al.[7] demonstrated that hederagenin administration ameliorates adriamycin-induced podocyte injury and glomerulosclerosis that improve renal function, as evidenced by reduced creatinine and urea levels. Furthermore, hederagenin treatment restored dysregulated CD4+/CD8+ T-cell ratio and attenuated tissue inflammation. Mechanistically, the authors provided compelling evidence that suppressing JAK/STAT pathway underlies these therapeutic effects. The pathogenesis of glomerulonephritis and nephrotic syndrome is primarily driven by podocyte injury, whether due to primary or secondary, immune or non-immune, or congenital or acquired factors, resulting in glomerular filtration barrier dysfunction and subsequent proteinuria, including albuminuria.[10] Therefore, both proteinuria and hypoalbuminemia are key diagnostic and prognostic indicators of glomerulonephritis and nephrotic syndrome. In this article, hederagenin administration can partially recover hypoalbuminemia in adriamycin-induced mice. However, it would be more valuable to ascertain the therapeutic potential of hederagenin to treat glomerulonephritis or nephrotic syndrome by assessing its efficacy in reducing proteinuria or albuminuria. Ectopic inflammation plays a pivotal role in the progression of glomerulonephritis.[10] In this study, it effectively suppressed the expression of pro-inflammatory cytokines including interleukin-1β (IL-1β) and IL-6 while rebalancing T-cell populations. These findings, taken alongside the podocyte-protective effects of hederagenin, suggest that the hederagenin holds promise as a therapeutic candidate for glomerulonephritis. However, further validation in additional animal models and CKD patients, such as membranous nephropathy and IgAN, is warranted to strengthen these findings. Moreover, urgent efforts are required to bridge the gap between pre-clinical and clinical trials and thus establish novel CKD therapeutic breakthroughs. As a pentacyclic triterpenoid, hederagenin is extremely water-insoluble,[6] indicating that a proper solvent is required. These shortages somehow compromise the translational value of hederagenin. To overcome these limitations, the structural modification of hederagenin should be performed, as was done in a study of its potential anti-tumor properties.[6] In conclusion, hederagenin provides valuable insights into the therapeutic potential for glomerulonephritis and nephrotic syndrome. Future study should further explore CKD therapeutic potential, integrating insights from hederagenin.