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Podocytes play a pivotal role in maintaining glomerular filtration function through their interdigitated foot processes. However, the mechanisms that govern the podocyte cytoskeletal rearrangement remain unclear. Through analyzing the transcriptional profile of renal biopsy specimens from patients with diabetic nephropathy (DN) and control donors, we identify SLIT-ROBO ρGTPase-activating protein 2a (SRGAP2a) as one of the main hub genes strongly associated with proteinuria and glomerular filtration in type 2 DN. Immunofluorescence staining and Western blot analysis revealed that human and mouse SRGAP2a is primarily localized at podocytes and largely colocalized with synaptopodin. Moreover, podocyte SRGAP2a is downregulated in patients with DN and db/db mice at both the mRNA and the protein level. SRGAP2a reduction is observed in cultured podocytes treated with tumor growth factor-β or high concentrations of glucose. Functional and mechanistic studies show that SRGAP2a suppresses podocyte motility through inactivating RhoA/Cdc42 but not Rac1. The protective role of SRGAP2a in podocyte function also is confirmed in zebrafish, in which knockdown of SRGAP2a, a SRGAP2 ortholog in zebrafish, recapitulates podocyte foot process effacement. Finally, increasing podocyte SRGAP2a levels in db/db mice through administration of adenovirus-expressing SRGAP2a significantly mitigates podocyte injury and proteinuria. The results demonstrate that SRGAP2a protects podocytes by suppressing podocyte migration., (© 2017 by the American Diabetes Association.)

Despite intensive glucose control or blood pressure control, the remission of proteinuria in patients with diabetic nephropathy remains extremely low. Tacrolimus has been successful in treating immune-related and genetic-related nephropathy, providing a feasible method to reduce proteinuria and podocyte damage in patients with diabetic nephropathy. However, doctors do not know how to avoid the risk of increased blood glucose levels and infection induced by tacrolimus. Here, we developed a RLD-sericin-tacrolimus conjugate (rs-TAC PDC), that specifically targets delivery of tacrolimus and sericin to podocytes. Administration of the rs-TAC PDC increases the levels of tacrolimus and serine in podocyte, and alleviates podocyte damage and albuminuria in diabetic nephropathy mice, with a better th44erapeutic effect than tacrolimus or serine alone. Mechanistically, tacrolimus restores the podocyte cytoskeleton, and inhibits the IL17 signalling pathway, and sericin promotes endogenous H 2 S production and reduces oxidative stress. Both of tacrolimus and serine work synergistically to protect podocyte from damage. On the other hand, the rs-TAC PDC reduces the accumulation of tacrolimus in the pancreas, lymph nodes, and thymus, subsequently reducing the risk of exacerbating hyperglycaemia and infection. Overall, the rs-TAC PDC provides better therapeutic effects and fewer side effects than tacrolimus alone in the treatment of diabetic nephropathy. [Display omitted] • The rs-TAC PDC consists of RLD, sericin and tacrolimus. • The rs-TAC PDC increases intracellular tacrolimus and serine levels in podocytes. • The rs-TAC PDC alleviates podocyte damage with a better effect than tacrolimus or serine alone. • The rs-TAC PDC reduces accumulation of tacrolimus in the pancreas, lymph nodes, and thymus. • The rs-TAC PDC avoids exacerbating hyperglycaemia and infection in diabetic nephropathy mice compared to tacrolimus. [ABSTRACT FROM AUTHOR]

Cellular injury caused by stimuli plays an important role in the progression of various diseases including acute and chronic kidney diseases. The dynamic transcriptional regulation responding to stimuli underlies the important mechanism of injury. In this study, we investigated the regulatory elements and their dynamic activities in kidney tubular epithelial cells. We captured the chromatin accessibility and gene expression with ATAC‐seq and RNA sequencing under a variety of extracellular stimuli including H2O2, TGF‐β1, and FG4592 which is an agonist of hypoxia‐inducible factor. Our results revealed both condition‐specific and condition‐shared transcription regulation. Interestingly, the shared regulation program revealed that the key transcription factor HNF1B‐mediated cellular reprogramming leads to a common change among the stimuli. We found the HNF1B regulatory network was significantly disrupted in various kidney diseases. [ABSTRACT FROM AUTHOR]