Chronic kidney disease (CKD) is one of the major global health concerns and is responsible for end‐stage renal disease (ESRD) complications. Inflammation plays a pivotal role in the progression of CKD. In the present study, we evaluated the renoprotective effects of a potent immunomodulator steroidal lactone, Withaferin A (WfA), in an animal model of renal injury (unilateral ureteral obstruction, UUO) and further investigated if the inhibition of inflammatory signaling can be a useful approach to reduce renal injury. Animals were randomly divided into five groups: Sham control, UUO control, WfA control, WfA low dose (1 mg/kg), and WfA high dose (3 mg/kg). Oxidative stress was measured by the estimation of reduced glutathione and lipid peroxidation levels. H&E and Picrosirius Red staining were performed to assess the extent of histological damage and collagen deposition. Furthermore, the molecular mechanism of the WfA effects was explored by immunohistochemistry, enzyme‐linked immunosorbent assay, multiplex analysis of transforming growth factor β (TGF‐β) pathway, and an array of inflammatory cytokines/chemokines. Interestingly, our pharmacological intervention significantly attenuated tissue collagen, inflammatory signaling, and macrophage signaling. WfA intervention abrogated the inflammatory signaling as evident from the modulated levels of chemokines and cytokines. The levels of TGF‐β along with downstream signaling molecules were also attenuated by WfA treatment as revealed by inhibition in the expression of TGF‐β1, TGF‐β2, p‐Smad2, p‐Smad3, total Smad4, p‐Akt, and p‐ERK. We, to the best of our knowledge, prove for the first time that WfA has potential renoprotective activity against UUO‐induced nephropathy due to its outstanding anti‐inflammatory properties.

Chronic kidney disease (CKD) has wide prevalence globally that affects a considerable population and has renal fibrosis (RF) as a hallmark feature. RF is characterized by abnormal deposition of extracellular matrix (ECM) in the interstitial space of renal tissue. There are only few studies where nanoparticles (NPs) were used for targeting the kidney mainly due to their sizedependent constraints. Further, most of the studies have been carried out in healthy animals. As the diseased kidney becomes susceptible to accumulation of nanoparticles, we hypothesized that nanoparticles (size ∼10 nm) could reach the kidney and might provide protective effects due to their inherent properties. We investigated the protective effects of cerium oxide nanoparticles (CONPs) with promising antioxidant activity in a CKD model. We, to the best of our knowledge, are first to report that CONPs abrogated RF by inhibiting transforming growth factor-β (TGF-β) signaling and epithelial−mesenchymal transition (EMT) in a fibrotic kidney.