Novel targets of antifibrotic and anti-inflammatory treatment in CKD

Abstract

Chronic kidney disease (CKD) is becoming a worldwide epidemic, driven largely by the dramatic rise in the prevalence of diabetes and obesity. Novel targets and treatments for CKD are, therefore, desperately needed—to both mitigate the burden of this disease in the general population and reduce the necessity for renal replacement therapy in individual patients. This Review highlights new insights into the mechanisms that contribute to CKD, and approaches that might facilitate the development of disease-arresting therapies for CKD. Particular focus is given to therapeutic approaches using antifibrotic agents that target the transforming growth factor β superfamily. In addition, we discuss new insights regarding the roles of vascular calcification, the NADPH oxidase family, and inflammation in the pathogenesis of CKD. We also highlight a new understanding regarding kidney energy sensing pathways (AMPK, sirtuins, and mTOR) in a variety of kidney diseases and how they are linked to inflammation and fibrosis. Finally, exciting new insights have been made into the role of mitochondrial function and mitochondrial biogenesis in relation to progressive kidney disease. Prospective therapeutics based on these findings will hopefully renew hope for clinicians and patients in the near future.

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

“…Moshe Levy et al [57] showed, in agreement with other studies, in both insulin deficient and insulin intact db/db animals, that SGLT2 inhibition results in a decrease in proteinuria and inflammation in the kidney. In addition, they showed that these beneficial effects are associated with significant decreases in mesangial expansion, accumulation of extracellular matrix proteins, fibrillary collagens, and prevention of podocyte loss, which are the hallmarks of diabetic nephropathy [62].…”

“…Since SGLT2 inhibitors act via a different mechanism than other oral anti-hyperglycemic drugs, they can be first line treatment in T2DM and DN in the future [62,65].…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…A number of agents which more or less specifically inhibit TGF-are in clinical trials, including fresolimumab (a TGFantibody), pirfenidone, tranilast and tranilast analogues (20,21). Little data are available so far and none of the clinical trials has been performed in the transplant allograft situation.…”

“…TGF-bs are widely expressed and act on almost every cell type by engaging signaling molecules of the Smad and non-Smad families such as small GTPase Ras/Rho molecules. A large number of therapeutic options to interfere with TGF-bioactivity has been tested in preclinical studies including antagonistic antibodies, soluble receptor forms, agents that inhibit downstream intracellular signaling molecules (in particular Smads), RNA interference and targeting of TGF--induced micro-RNAs (20,255,(257)(258)(259)(260). Other antifibrotic interventions in the system are focused on modulators of TGF-bioactivity, such as BMP-7 or BMP antagonists such as USAG-1 (253,261,262).…”

“…Thus, we present a subjective and non-comprehensive selection of recent work, focusing, wherever possible, on the allograft situation. The interested reader is referred to a number of recent reviews for further information (20)(21)(22)(23)(24)(25)(26).…”