Available Therapies for RCC and CKD

In clinical practice, the two pathologies show different outcomes. If detected at an early stage, RCC treatment offers a good prognosis. Tumor resection is the first-line treatment for limited RCC and allows the removal of the tumor with limited impact on renal function. Advanced RCC is associated with a poorer prognosis, with approximately one-third of patients with RCC diagnosed with metastatic tumors.CKD is a progressive disease with very limited treatment options. It is estimated that approximately one in ten adults worldwide experience some form of chronic kidney disease. Managing lifestyle through diet and blood pressure control and maintaining physical activity remain the best options for minimizing the impact and slowing the decline of kidney function. Nevertheless, CKD often leads to kidney failure requiring renal replacement therapy, starting with dialysis and eventually leading to a kidney transplant. Renal cell carcinoma is insidious and challenging to diagnose because it is asymptomatic in its initial stages. Even in the intermediate to advanced stages, this pathology does not appear to interfere with normal renal function, rendering the commonly used markers to assess renal function, such as glomerular filtration rate (GFR), anemia, and decreased systemic sodium, ineffective in detecting it. Most cases of RCC are found incidentally when patients undergo diagnostic imaging (e.g., ultrasound, tomography) for unrelated reasons.

Usually, tumors are detected in people at high risk of renal insufficiency (e.g. hypertension, diabetes) and these patients need to be tested for kidney damage. In the last two decades, the treatment of RCC, namely in its advanced stages, has seen tremendous improvements. Patients with previously poor clinical prognoses have mainly benefited from two new classes of drugs, immune checkpoint inhibitors (ICI) and poly tyrosine kinase inhibitors (TKI). ICI are large bio immunotherapeutic molecules, either whole antibodies or antigen-binding fragments (Fab), that block the binding of checkpoint receptors in t cells to their respective membrane ligands. Checkpoint receptors regulate the immune response, helping t cells to distinguish between autologous, healthy, and foreign cells under normal physiological conditions and preventing disproportionate immune cascade reactions. RCC cells protect themselves from the immune system by presenting specific checkpoint ligands on their membranes. ICIs promote t-cell activation and induce cell death pathways in tumor cells by exposing RCC as disease tissue. TKI is a small molecule drug that targets the activity of specific tyrosine kinase proteins that regulate key cellular processes. TKIs that are effective in the treatment of RCC target different subtypes of VEGF receptors and block their angiogenic activity. These drugs prevent the vascular endothelial cells from responding to VEGF secreted by RCC, impairing the angiogenic activity and blood supply to the tumor and thus impeding tumor proliferation. In addition, mammalian targets of rapamycin (mTOR) inhibitors are used to treat RCC [27]. mTOR pathway is an upstream regulator of VEGF synthesis and plays a central role in cell proliferation and differentiation [28]. Its inhibition blocks the release of VEGF and hinders the proliferation of cancer cells, hence the benefit of mTOR inhibitors in RCC. Current first-line pharmacological interventions for the treatment of RCC, depending on disease severity and risk factors at diagnosis, include a combination of ICI and TKI therapy or different ICI molecules (Nivolumab and Ipilimumab) [29]. As of 2021, the European Medicines Agency (EMA) and the US Federal Drug Administration (FDA) approved about 15 molecules as single agents or in combination for the treatment of RCC [30,31].

Click here to know the benefits of Cistanche for Kidneys

In contrast to this situation, the first molecule to treat the progression of CKD is FDA, approved in 2021. Dapagliflozin is a sodium-glucose transporter protein 2 (SLGT2) inhibitor developed (and approved) for the treatment of type 2 diabetes (T2D). It lowers blood glucose levels by preventing the reabsorption of filtered glucose by RPTEC in the kidneys. The drug was repurposed for the treatment of CKD after substantially reducing the risk of renal failure and the onset of end-stage renal disease in patients with or without T2D [32].In addition to blocking glucose uptake, SLGT2 inhibition in RPTEC reduces sodium uptake, thereby reducing the workload of the sodium-potassium- ATPase (Na/ k - ATPase) efflux pump.Na/ k -ATPase is highly expressed in RPTEC and is essential for their physiology (e.g., maintenance of electrochemical gradients, activity consistent with SLGT2, and osmotic balance). It is estimated that these pumps consume more than one-third of cellular ATP production [33].The downregulation of Na/ k - ATPase activity appears to benefit renal physiology as it minimizes energy demand and, incidentally, O2 cell consumption. With reduced oxygen supply stress, HIF physiological regulation is restored and cells become more resilient to hypoxic events. In addition, reduced sodium secretion into the renal medulla relieves vasoconstriction. This reduces the stress on endothelial cells, improving their function and minimizing vascular damage while restoring renal oxygen supply [34]. Dapagliflozin represents a direct pharmacological intervention against the progression of CKD; nevertheless, other therapies aimed at managing other diseases also contribute to the prevention of renal damage and the development of CKD. Antihypertensive drugs may exert a long-term protective effect on the kidney by minimizing the effects of hypertension and promoting vasodilation [35]. In addition, evidence also suggests that SLGT2 inhibitors are cardioprotective because of their anti-inflammatory and anti-fibrotic effects in cardiomyocytes derived from lower intracellular sodium levels [36]. One of the reasons why treatment options for CKD are allegedly very limited is our limited understanding of its pathophysiology. The decline in renal function with age affects the pharmacodynamics of several therapeutic agents, thus precluding their potential use in the treatment of CKD [37].

Prospective New Therapies for RCC

RCC, despite its complexity, has at its core a phenotypic dedifferentiation driven by the PDH-VHL-HIF axis, leading to high angiogenic activity. This fact, together with evidence from extensive cancer studies, has enabled the development of targeted therapies, not only for RCC but also for cancers with similar regulatory pathways [38,39]. Furthermore, the vast majority of RCC drugs and therapies currently in development are focused on novel ICI and TKI molecules and combinations of already approved drugs, respectively [34,35]. This illustrates the effectiveness of currently available therapies. Of note are the ongoing trials to investigate the effects of combining an ICI with an experimental cancer vaccine (NCT02950766). The aim of this new approach is to improve the efficacy of immunotherapy, including in patients with limited response to treatment [40]. Mutations in tumors produce neoantigens, which are proteins specific to individual cancers. In contrast to conserved immune-histocompatibility antigens shared in human populations, neoantigens are recognized by t cells as foreign entities and can trigger an immune response [41].

However, under normal circumstances, factors such as limited immune cell infiltration, tumor-derived t-cell suppression, and neoantigen turnover limit this response. Evidence from preclinical studies suggests that mRNA-based vaccines encoding neoantigens greatly amplify t-cell-mediated tumor cell death and maintain an adaptive immune response [42]. This effect was achieved thanks to the initiation of a large pool of t cells to recognize tumor cells expressing neoantigens and memory b cells. Given the unique nature of neoantigens, clinical trials of such new therapies require a personalized drug strategy in which tumor samples are analyzed and targeted neoantigens are sequenced to produce patient-specific mRNA vaccines [43].RCC, with its relatively stable mutation rate and a high proportion of neoantigens [44], is one of the more promising cancer types for ICI-mRNA vaccine combinations. The basic principle behind this strategy is to amplify and maintain the ICI immune response by activating large numbers of t cells to target tumors. This can potentially overcome the poor ICI response in certain patients (e.g., those with depressed immune systems) by amplifying t cells directly to the tumor, bypassing the tumor immunosuppressive microenvironment. One of the challenges of this new approach is tumor heterogeneity and the chance of neoantigen depletion, where only tumor cells with specific neoantigens are targeted, while other mutated cells proliferate unharmed [45]. Tools that can predict neoantigen sequences and vaccines that include multiple targets could overcome these problems, as well as the consequences of early detection of RCC and minimizing aggressive cancer phenotypes [46].

As of 2021, current phase I clinical trials are in the recruitment phase and are expected to produce results in the next few years. Due to the fact that no RNA-based vaccine is currently approved for cancer treatment and the challenges of developing and producing patient-specific molecules within the timeframe required for effective treatment, it can be argued that the practical application of ICI-mRNA vaccines is still several years away. Nevertheless, this innovative therapy would represent another major improvement in the treatment of patients with RCC.

standardized Cistanche

Perspective on the Use of New Drugs Modalities in RCC and CKD

Experimental molecules (often referred to as small molecules) with significantly different biological activity, physicochemical properties, and pharmacokinetics than conventional molecules are often informally referred to as new drug models (NDM) [63].NDM include a very diverse collection of molecules that have attracted extensive attention from pharmaceutical manufacturers due to their potential for very high efficacy and marginal toxicity [64].

A prominent class of NDMs are RNA-based drugs; they can be designed to upregulate or block the expression of target proteins [65]. The above-mentioned mRNA vaccine against RCC can be considered an RNA drug. Antisense oligonucleotides (ASOs) are highly stable, short, single-stranded oligonucleotide sequences that bind mRNA and block protein translation.ASOs can be tailored to virtually block the expression of proteins of interest [66]. These molecules are hindered by limited distribution and tend to accumulate in tissues while having a very slow elimination rate. Interestingly, ASO accumulates in large quantities in the kidney, mainly in the proximal tubules, through an endocytic mechanism that is not yet fully understood [67]. Therefore, ASO is considered to be an easy vehicle to reach therapeutic targets in RPTEC, and the latest generation of ASO has shown remarkable renal safety [68]. Autosomal polycystic kidney disease (APKD), a genetic disorder characterized by the formation of large fluid-filled renal cysts, can lead to renal failure [69]. Its genetic roots and the molecular mechanisms of pathogenesis are reasonably well understood [70]. In a homozygous mouse model of APKD, ASO targeting the mTOR complex normalizes renal function while reducing body weight and cyst size [71]. Alport syndrome (AS) is another genetic disorder leading to renal failure characterized by a lack of type IV collagen, resulting in glomerulonephritis [72].ASO was designed to truncate the COL4A5 gene (type IV collagen α -5 chain) expression and successfully improved the survival rate of X-linked AS male animal models [73]. In the field of renal cancer, ASO targeting VEGF successfully promoted the remission of RCC xenograft tumors [74]. Although preclinical data are promising, the development of ASO is complex and requires the identification of highly specific genetic targets. Despite the improved safety profile of ASO, concerns remain about the long-term accumulated pathological impact of ASO in RPTEC [75], which is the main reason for the slow progress of ASO clinical studies. In the search for CKD targets, genetic variants of apolipoprotein L1 (APOL1) have been widely associated with the development of CKD [76]. expression of APOL1 leads to loss of podocytes and, incidentally, renal function, and a recently initiated phase I trial (NCT04269031) will begin to evaluate the potential of anti-APOL1 ASO for the treatment of CKD [77].

the effects of Cistanche on kidney

Anti-lipotropins are genetically modified lipotropins, a family of small human-binding proteins, which are artificial proteins that can be used as antibody mimics [78]. An advantage of these synthetic peptides is their small size relative to conventional monoclonal antibodies (about 1/8 of the size). This fact explains the improved tissue permeation properties of anti-penicillin, which facilitates drug delivery and better clearance properties and minimizes potential side effects due to prolonged exposure [79]. In a first human trial involving patients with kidney cancer, anti-VEGF anti-aspirin effectively rendered VEGF undetectable in the body circulation [80]. Subsequent preclinical studies showed that the anti-alien inhibited VEGF-mediated endothelial cell proliferation, decreased microvascular density, and increased vascular permeability. Relative to the approved anti-VEGF monoclonal antibody bevacizumab, the anti-alien analog showed a higher safety profile, with no observed platelet aggregation or thrombosis [81].

Proteolysis Targeting Chimeras (PROTAC) are bifunctional molecules that mediate selective protein degradation [82].PROTAC consists of two protein binding domains linked together; one structural domain interacts with E3 ubiquitin ligases and the other interacts with any given protein [83 ]. Thus, PROTAC is designed to bind proteins of interest and target them for degradation by activating the ubiquitin-proteasome system.PROTAC is highly specific and efficient in knocking down target proteins, has pharmacokinetic properties closer to those of small molecules relative to other novel drugs, and does not accumulate in tissues over time [84]. There is a growing interest in these molecules in oncology research, considering their potential to remove upregulated or aberrant proteins that contribute to the malignant phenotype [85].PROTAC research is still in its infancy, with the first report of an E3 ligase chimera in 2008 [86]. Nevertheless, the opportunity to develop therapies for common diseases that lack effective treatments has driven interest in PROTACS [87]. This is evidenced by the development of the androgen receptor degrader ARV-110, which is currently in a phase II trial for the treatment of desmoplastic-resistant prostate cancer (NCT03888612) [88]. There are limited studies on the application of PROTACS to kidney pathology. Of note is the development of the recruitment to PROTACS [89]. Although VHL degraders may be ineffective in renal cell carcinomas with loss of VHL function [90], they may bypass VHL activity and directly target HIF to ubiquitin ligases. On the other hand, small molecule inhibitors of VHL-HIF interactions, such as VH298, have been developed. These molecules mimic hypoxia and stabilize HIF activity [91] and represent a step forward in our toolbox to better understand and develop pharmacological interventions for the treatment of renal hypoxia, a common root cause of RCC and CKD.

Herbal Cistanche

Conclusions

Although the introduction of targeted immunotherapies has greatly improved the treatment of RCC, no significant progress has been made in the treatment of CKD. Nevertheless, the next generation of drugs may lead to such breakthroughs. A better and more comprehensive understanding of the pathophysiology of renal disease is driving the identification of new therapeutic targets and helping to reveal the disposition, metabolism, and pharmacokinetics of DMPK, as well as the safety and efficacy of a novel, less permeable, and more chemically stable molecules. The genetic and molecular mechanisms controlling pathologies such as APKD, as and even RCC are now fairly well understood, a factor that has greatly facilitated the design and development of specific therapies. the heterogeneity of CKD effectively represents a collection of different renal conditions, which poses a challenge to elucidating druggable targets. Although the role of fibrosis in CKD is now evident, its contribution to the onset and progression of RCC remains elusive. On the one hand, dealing with fibrosis in CKD may improve renal function and prevent its decline by preserving renal tubular structures. On the other hand, fibrosis may be involved in the inflammatory firewall of RCC self-protection, and reducing it may expose tumors and promote immunotherapeutic activity. Identifying common factors and regulatory pathways in CKD and RCC, such as hypoxic response modulation, is a step towards discovering biomarkers that can be used for early diagnosis and differentiation between the two pathologies.

Why does Cistanche extract benefit the kidneys?

Cistanche tubulosa is a kind of rare Chinese medicinal material parasitizing in deserts. Contains a large number of phenylethanoid glycosides, Echinacoside, and Verbascoside. These ingredients are very helpful to human kidney function. Long-term and rational use of Cistanche extract has unexpected benefits for the kidney.

REFERENCES

27. Battelli, C.; Cho, D.C. mTOR inhibitors in renal cell carcinoma. Therapy 2011, 8, 359.

28. Dodd, K.M.; Yang, J.; Shen, M.H.; Sampson, J.R.; Tee, A.R. mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene 2015, 34, 2239–2250.

29. Bedke, J.; Albiges, L.; Capitanio, U.; Giles, R.H.; Hora, M.; Lam, T.B.; Ljungberg, B.; Marconi, L.; Klatte, T.; Volpe, A.; et al. 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor–based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care. Eur. Urol. 2021, 80, 393–397.

30. Khetani, V.V.; Portal, D.E.; Shah, M.R.; Mayer, T.; Singer, E.A. Combination drug regimens for metastatic clear cell renal cell carcinoma. World J. Clin. Oncol. 2020, 11, 541.

31. Hemminki, O.; Perlis, N.; Bjorklund, J.; Finelli, A.; Zlotta, A.R.; Hemminki, A. Treatment of Advanced Renal Cell Carcinoma: Immunotherapies Have Demonstrated Overall Survival Benefits While Targeted Therapies Have Not. Eur. Urol. Open Sci. 2020, 22, 61–73.

32. Wheeler, D.C.; Toto, R.D.; Stefánsson, B.V.; Jongs, N.; Chertow, G.M.; Greene, T.; Hou, F.F.; McMurray, J.J.; Pecoits-Filho, R.; Correa-Rotter, R.; et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int. 2021, 100, 215–224.

33. Weigand, K.M.; Swarts, H.G.; Fedosova, N.U.; Russel, F.G.; Koenderink, J.B. Na, K-ATPase activity modulates Src activation: A role for ATP/ADP ratio. Biochim. Biophys. Acta (BBA)-Biomembr. 2012, 1818, 1269–1273.

34. Salvatore, T.; Caturano, A.; Galiero, R.; Di Martino, A.; Albanese, G.; Vetrano, E.; Sardu, C.; Marfella, R.; Rinaldi, L.; Sasso, F.C. Cardiovascular Benefits from Gliflflozins: Effects on Endothelial Function. Biomedicines 2021, 9, 1356.

35. Navis, G.; Faber, H.J.; de Zeeuw, D.; de Jong, P.E. ACE Inhibitors and the Kidney. Drug Saf. 1996, 15, 200–211.

36. Palmiero, G.; Cesaro, A.; Vetrano, E.; Pafundi, P.; Galiero, R.; Caturano, A.; Moscarella, E.; Gragnano, F.; Salvatore, T.; Rinaldi, L.; et al. Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects. Int. J. Mol. Sci. 2021, 22, 5863.

37. Caturano, A.; Galiero, R.; Pafundi, P.C. Atrial Fibrillation and Stroke. A Review on the Use of Vitamin K Antagonists and Novel Oral Anticoagulants. Medicina 2019, 55, 617.

38. Mollica, V.; Di Nunno, V.; Gatto, L.; Santoni, M.; Cimadamore, A.; Cheng, L.; López-Beltrán, A.; Montironi, R.; Pisconti, S.; Battelli, N.; et al. Novel Therapeutic Approaches and Targets Currently Under Evaluation for Renal Cell Carcinoma: Waiting for the Revolution. Clin. Drug Investig. 2019, 39, 503–519.

39. Kim, H.; Shim, B.Y.; Lee, S.-J.; Lee, J.Y.; Lee, H.-J.; Kim, I.-H. Loss of Von Hippel–Lindau (VHL) Tumor Suppressor Gene Function: VHL–HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC). Int. J. Mol. Sci. 2021, 22, 9795.

40. Liao, J.-Y.; Zhang, S. Safety and Efficacy of Personalized Cancer Vaccines in Combination With Immune Checkpoint Inhibitors in Cancer Treatment. Front. Oncol. 2021, 11, 1899.

41. Jiang, T.; Shi, T.; Zhang, H.; Hu, J.; Song, Y.; Wei, J.; Ren, S.; Zhou, C. Tumor neoantigens: From basic research to clinical applications. J. Hematol. Oncol. 2019, 12, 1–13.

42. Fang, Y.; Mo, F.; Shou, J.; Wang, H.; Luo, K.; Zhang, S.; Han, N.; Li, H.; Ye, S.; Zhou, Z.; et al. A pan-cancer clinical study of personalized neoantigen vaccine monotherapy in treating patients with various types of advanced solid tumors. Clin. Cancer Res. 2020, 26, 4511–4520.

43. Blass, E.; Ott, P.A. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat. Rev. Clin. Oncol. 2021, 18, 215–229.

44. Black, C.M.; Armstrong, T.D.; Jaffee, E.M. Apoptosis-Regulated Low-Avidity Cancer-Specifific CD8+ T Cells Can Be Rescued to Eliminate HER2/neu–Expressing Tumors by Costimulatory Agonists in Tolerized Mice. Cancer Immunol. Res. 2014, 2, 307–319.

45. Kim, T.-M.; Laird, P.W.; Park, P.J. The Landscape of Microsatellite Instability in Colorectal and Endometrial Cancer Genomes. Cell 2013, 155, 858–868.

46. De Mattos-Arruda, L.; Vazquez, M.; Finotello, F.; Lepore, R.; Porta, E.; Hundal, J.; Amengual-Rigo, P.; Ng, C.; Valencia, A.; Carrillo, J.; et al. Neoantigen prediction and computational perspectives towards clinical benefit: Recommendations from the ESMO Precision Medicine Working Group. Ann. Oncol. 2020, 31, 978–990.

47. Yuan, Q.; Zhang, H.; Deng, T.; Tang, S.; Yuan, X.; Tang, W.; Xie, Y.; Ge, H.; Wang, X.; Zhou, Q.; et al. Role of Artificial Intelligence in Kidney Disease. Int. J. Med Sci. 2020, 17, 970–984.

48. Wiatrak, M.; Iso-Sipila, J. Simple Hierarchical Multi-Task Neural End-To-End Entity Linking for Biomedical Text. In Proceedings of the 11th International Workshop on Health Text Mining and Information Analysis, Online, 20 November 2020; pp. 12–17.

49. Rayego-Mateos, S.; Valdivielso, J.M. New therapeutic targets in chronic kidney disease progression and renal fibrosis. Expert Opin. Ther. Targets 2020, 24, 655–670.

50. Reisman, S.A.; Chertow, G.M.; Hebbar, S.; Vaziri, N.D.; Ward, K.W.; Meyer, C.J. Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney. J. Am. Soc. Nephrol. 2012, 23, 1663–1673.

51. De Zeeuw, D.; Akizawa, T.; Audhya, P.; Bakris, G.L.; Chin, M.; Christ-Schmidt, H.; Goldsberry, A.; Houser, M.; Krauth, M.; Heerspink, H.J.L.; et al. Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease. N. Engl. J. Med. 2013, 369, 2492–2503.

52. Chertow, G.M.; Appel, G.B.; Andreoli, S.; Bangalore, S.; Block, G.A.; Chapman, A.B.; Chin, M.P.; Gibson, K.L.; Goldsberry, A.; Iijima, K.; et al. Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome. Am. J. Nephrol. 2021, 52, 180–189.

53. Yoh, K.; Itoh, K.; Enomoto, A.; Hirayama, A.; Yamaguchi, N.; Kobayashi, M.; Morito, N.; Koyama, A.; Yamamoto, M.; Takahashi, S. Nrf2-defificient female mice develop lupus-like autoimmune nephritis. Kidney Int. 2001, 60, 1343–1353.

54. Bellezza, I.; Giambanco, I.; Minelli, A.; Donato, R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim. Biophys. Acta (BBA)-Mol. Cell Res. 2018, 1865, 721–733.

55. Meng, X.-M.; Nikolic-Paterson, D.J.; Lan, H.Y. TGF-β: The master regulator of fibrosis. Nat. Rev. Nephrol. 2016, 12, 325–338.

56. Margaritopoulos, G.A.; Trachalaki, A.; Wells, A.U.; Vasarmidi, E.; Bibaki, E.; Papastratigakis, G.; Detorakis, S.; Tzanakis, N.; Antoniou, K.M. Pirfenidone improves survival in IPF: Results from a real-life study. BMC Pulm. Med. 2018, 18, 177.

57. Zhou, C.; Zeldin, Y.; Baratz, M.E.; Kathju, S.; Satish, L. Investigating the effects of Pirfenidone on TGF-β1 stimulated non-SMAD signaling pathways in Dupuytren’s disease-derived fibroblasts. BMC Musculoskelet. Disord. 2019, 20, 135.

58. Bedinger, D.; Lao, L.; Khan, S.; Lee, S.; Takeuchi, T.; Mirza, A.M. Development and characterization of human monoclonal antibodies that neutralize multiple TGFβ isoforms. mAbs 2016, 8, 389–404.

59. Voelker, J.; Berg, P.; Sheetz, M.; Duffifin, K.; Shen, T.; Moser, B.; Greene, T.; Blumenthal, S.S.; Rychlik, I.; Yagil, Y.; et al. Anti–TGF-β1 Antibody Therapy in Patients with Diabetic Nephropathy. J. Am. Soc. Nephrol. 2016, 28, 953–962.

60. Ruiz-Ortega, M.; Rupérez, M.; Esteban, V.; Rodriguez-Vita, J.; Sanchez-Lopez, E.; Carvajal, G.; Egido, J. Angiotensin II: A key factor in the inflammatory and fibrotic response in kidney diseases. Nephrol. Dial. Transplant. 2006, 21, 16–20.

61. Griffin, K.A.; Bidani, A.K. Progression of Renal Disease: Renoprotective Specificity of Renin-Angiotensin System Blockade. Clin. J. Am. Soc. Nephrol. 2006, 1, 1054–1065.

62. Jafar, T.H.; Schmid, C.H.; Landa, M.; Giatras, I.; Toto, R.; Remuzzi, G.; Maschio, G.; Brenner, B.M.; Kamper, A.; Zucchelli, P.; et al. Angiotensin-Converting Enzyme Inhibitors and Progression of Nondiabetic Renal Disease: A meta-analysis of patient-level data. Ann. Intern. Med. 2001, 135, 73–87.

63. Blanco, M.-J.; Gardinier, K.M. New Chemical Modalities and Strategic Thinking in Early Drug Discovery. ACS Med. Chem. Lett. 2020, 11, 228–231.

64. Tambuyzer, E.; Vandendriessche, B.; Austin, C.P.; Brooks, P.J.; Larsson, K.; Needleman, K.I.M.; Valentine, J.; Davies, K.; Groft, S.C.; Preti, R.; et al. Therapies for rare diseases: Therapeutic modalities, progress and challenges ahead. Nat. Rev. Drug Discov. 2020, 19, 93–111.

65. Wang, F.; Zuroske, T.; Watts, J.K. RNA therapeutics on the rise. Nat. Rev. Drug Discov. 2020, 19, 441–442.

66. Crooke, S.T. Molecular Mechanisms of Antisense Oligonucleotides. Nucleic Acid Ther. 2017, 27, 70–77.

67. Janssen, M.J.; Nieskens, T.T.G.; Steevels, T.A.M.; Caetano-Pinto, P.; den Braanker, D.; Mulder, M.; Ponstein, Y.; Jones, S.; Masereeuw, R.; Besten, C.D.; et al. Therapy with 2’-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption. Mol. Ther.-Nucleic Acids 2019, 18, 298–307.

68. Engelhardt, J.A. Comparative Renal Toxicopathology of Antisense Oligonucleotides. Nucleic Acid Ther. 2016, 26, 199–209.

69. Igarashi, P.; Somlo, S. Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2007, 18, 1371–1373.

70. Igarashi, P.; Somlo, S. Genetics and Pathogenesis of Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2002, 13, 2384–2398.

71. Ravichandran, K.; Zafar, I.; He, Z.; Doctor, R.B.; Moldovan, R.; Mullick, A.E.; Edelstein, C.L. An mTOR anti-sense oligonucleotide decreases polycystic kidney disease in mice with a targeted mutation in Pkd2. Hum. Mol. Genet. 2014, 23, 4919–4931.

72. Nozu, K.; Nakanishi, K.; Abe, Y.; Udagawa, T.; Okada, S.; Okamoto, T.; Kaito, H.; Kanemoto, K.; Kobayashi, A.; Tanaka, E.; et al. A review of clinical characteristics and genetic backgrounds in Alport syndrome. Clin. Exp. Nephrol. 2019, 23, 158–168.

73. Yamamura, T.; Horinouchi, T.; Adachi, T.; Terakawa, M.; Takaoka, Y.; Omachi, K.; Takasato, M.; Takaishi, K.; Shoji, T.; Onishi, Y.; et al. Development of an exon-skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5. Nat. Commun. 2020, 11, 1–8.

74. Shi, W.; Siemann, D.W. Inhibition of renal cell carcinoma angiogenesis and growth by antisense oligonucleotides targeting vascular endothelial growth factor. Br. J. Cancer 2002, 87, 119–126.

75. Chi, X.; Gatti, P.; Papoian, T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discov. Today 2017, 22, 823–833.

76. Friedman, D.J.; Pollak, M.R. APOL1 Nephropathy: From Genetics to Clinical Applications. Clin. J. Am. Soc. Nephrol. 2021, 16, 294–303.

77. Daehn, I.S.; Duffifield, J.S. The glomerular filtration barrier: A structural target for novel kidney therapies. Nat. Rev. Drug Discov. 2021, 20, 770–788.

78. Rothe, C.; Skerra, A. Anticalin® Proteins as Therapeutic Agents in Human Diseases. BioDrugs 2018, 32, 233–243.

79. Deuschle, F.-C.; Ilyukhina, E.; Skerra, A. Anticalin® proteins: From bench to bedside. Expert Opin. Biol. Ther. 2021, 21, 509–518.

80. Mross, K.; Richly, H.; Fischer, R.; Scharr, D.; Buechert, M.; Stern, A.; Gille, H.; Audoly, L.P.; Scheulen, M.E. First-in-Human Phase I Study of PRS-050 (Angiocal), an Anticalin Targeting and Antagonizing VEGF-A, in Patients with Advanced Solid Tumors. PLoS ONE 2013, 8, e83232.

81. Gille, H.; Hülsmeyer, M.; Trentmann, S.; Matschiner, G.; Christian, H.J.; Meyer, T.; Amirkhosravi, A.; Audoly, L.P.; Hohlbaum, A.M.; Skerra, A. Functional characterization of a VEGF-A-targeting Anticalin, prototype of a novel therapeutic human protein class. Angiogenesis 2016, 19, 79–94.

82. He, Y.; Khan, S.; Huo, Z.; Lv, D.; Zhang, X.; Liu, X.; Yuan, Y.; Hromas, R.; Xu, M.; Zheng, G.; et al. Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies. J. Hematol. Oncol. 2020, 13, 1–24.

83. Sakamoto, K.M.; Kim, K.B.; Kumagai, A.; Mercurio, F.; Crews, C.M.; Deshaies, R.J. Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA 2001, 98, 8554–8559.

84. Cantrill, C.; Chaturvedi, P.; Rynn, C.; Schafflfland, J.P.; Walter, I.; Wittwer, M.B. Fundamental aspects of DMPK optimization of targeted protein degraders. Drug Discov. Today 2020, 25, 969–982.

85. Khan, S.; He, Y.; Zhang, X.; Yuan, Y.; Pu, S.; Kong, Q.; Zheng, G.; Zhou, D. PROteolysis Targeting Chimeras (PROTACs) as emerging anticancer therapeutics. Oncogene 2020, 39, 4909–4924.

86. Neklesa, T.K.; Winkler, J.D.; Crews, C.M. Targeted protein degradation by PROTACs. Pharmacol. Ther. 2017, 174, 138–144.

87. Sun, X.; Gao, H.; Yang, Y.; He, M.; Wu, Y.; Song, Y.; Tong, Y.; Rao, Y. PROTACs: Great opportunities for academia and industry. Signal Transduct. Target. Ther. 2019, 4, 1–33.

88. Petrylak, D.P.; Gao, X.; Vogelzang, N.J.; Garfifield, M.H.; Taylor, I.; Moore, M.D.; Peck, R.A.; Burris, H.A. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI). J. Clin. Oncol. 2020, 38.

89. Smith, B.E.; Wang, S.L.; Jaime-Figueroa, S.; Harbin, A.; Wang, J.; Hamman, B.D.; Crews, C.M. Differential PROTAC substrate specificity dictated by the orientation of recruited E3 ligase. Nat. Commun. 2019, 10, 1–13.

90. Yang, G.; Shi, R.; Zhang, Q. Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression. Int. J. Mol. Sci. 2020, 21, 8162.

91. Frost, J.; Galdeano, C.; Soares, P.; Gadd, M.; Grzes, K.M.; Ellis, L.; Epemolu, O.; Shimamura, S.; Bantscheff, M.; Grandi, P.; et al. The potent and selective chemical probe of hypoxic signaling downstream of HIF-α hydroxylation via VHL inhibition. Nat. Commun. 2016, 7, 1–12.

3.martin.burchardt@med.uni-greifswald.de (M.B.)

* Correspondence: ingmar.wolff@med.uni-greifswald.de