B7-1 mediates podocyte injury and glomerulosclerosis through communication with Hsp90ab1-LRP5-β-catenin pathway.
Cell death and differentiation
Podocyte injury is a hallmark of glomerular diseases; however, the underlying mechanisms remain unclear. B7-1 is increased in injured podocytes, but its intrinsic role is controversial. The clinical data here revealed the intimate correlation of urinary B7-1 with severity of glomerular injury. Through transcriptomic and biological assays in B7-1 transgenic and adriamycin nephropathy models, we identified B7-1 is a key mediator in podocyte injury and glomerulosclerosis through a series of signal transmission to β-catenin. Using LC-MS/MS, Hsp90ab1, a conserved molecular chaperone, was distinguished to be an anchor for transmitting signals from B7-1 to β-catenin. Molecular docking and subsequent mutant analysis further identified the residue K69 in the N terminal domain of Hsp90ab1 was the key binding site for B7-1 to activate LRP5/β-catenin pathway. The interaction and biological functions of B7-1-Hsp90ab1-LRP5 complex were further demonstrated in vitro and in vivo. We also found B7-1 is a novel downstream target of β-catenin. Our results indicate an intercrossed network of B7-1, which collectively induces podocyte injury and glomerulosclerosis. Our study provides an important clue to improve the therapeutic strategies to target B7-1.
10.1038/s41418-022-01026-8
Btg2 Promotes Focal Segmental Glomerulosclerosis via Smad3-Dependent Podocyte-Mesenchymal Transition.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Podocyte injury plays a critical role in the progression of focal segmental glomerulosclerosis (FSGS). Here, it is reported that B-cell translocation gene 2 (Btg2) promotes Adriamycin (ADR)-induced FSGS via Smad3-dependent podocyte-mesenchymal transition. It is found that in FSGS patients and animal models, Btg2 is markedly upregulated by podocytes and correlated with progressive renal injury. Podocyte-specific deletion of Btg2 protected against the onset of proteinuria and glomerulosclerosis in ADR-treated mice along with inhibition of EMT markers such as α-SMA and vimentin while restoring epithelial marker E-cadherin. In cultured MPC5 podocytes, overexpression of Btg2 largely promoted ADR and TGF-β1-induced EMT and fibrosis, which is further enhanced by overexpressing Btg2 but blocked by disrupting Btg2. Mechanistically, Btg2 is rapidly induced by TGF-β1 and then bound Smad3 but not Smad2 to promote Smad3 signaling and podocyte EMT, which is again exacerbated by overexpressing Btg2 but blocked by deleting Btg2 in MPC5 podocytes. Interestingly, blockade of Smad3 signaling with a Smad3 inhibitor SIS3 is also capable of inhibiting Btg2 expression and Btg2-mediated podocyte EMT, revealing a TGF-β/Smad3-Btg2 circuit mechanism in Btg2-mediated podocyte injury in FSGS. In conclusion, Btg2 is pathogenic in FSGS and promotes podocyte injury via a Smad3-dependent EMT pathway.
10.1002/advs.202304360
Selonsertib Enhances Kidney Protection Beyond Standard of Care in a Hypertensive, Secondary Glomerulosclerosis CKD Model.
Kidney360
Background:Despite widespread use of renin-aldosterone-angiotensin system inhibitors and the benefits of lowering glomerular pressure in patients with CKD, there remains a major unmet need for therapies targeting underlying causes of CKD progression. Apoptosis signal-regulating kinase 1 (ASK1) promotes apoptosis and glomerulosclerosis, and is implicated in the progression of diabetic kidney disease (DKD), a major cause of CKD. Selonsertib is a selective ASK1 inhibitor currently in clinical development for the treatment of DKD. We examined the added benefits of selonsertib on existing glomerulosclerosis and related molecular pathways in the nondiabetic 5/6 nephrectomy (5/6 Nx) rat model in combination with the angiotensin-converting enzyme inhibitor (ACEI) enalapril. Methods:Male Sprague Dawley rats underwent 5/6 Nx with kidney biopsy 8 weeks later for assessment of glomerulosclerosis, and were randomized to four treatment groups with equal glomerulosclerosis: selonsertib, enalapril, combination (selonsertib plus enalapril), and untreated controls. Serum creatinine, systolic BP (SBP), and urinary albumin were measured at intervals. Animals were euthanized at week 12 for histologic, biochemical, and molecular analyses. Results:All rats developed hypertension, albuminuria, and glomerulosclerosis by week 8. Kidney function further declined, and glomerulosclerosis and albuminuria progressively increased in controls from week 8 to 12. Enalapril treatment alone from week 8 to 12 reduced SBP versus controls, decreased albuminuria, and resulted in numerically lower glomerulosclerosis. Selonsertib alone had no effect on SBP but preserved kidney function. Combined treatment significantly reduced glomerulosclerosis, with more regression than either monotherapy. Enalapril treatment resulted in fewer interstitial macrophages, whereas selonsertib treatment reduced apoptosis and podocyte loss. RNA-seq revealed that combined treatment influenced pathways related to extracellular matrix and wound healing. Conclusions:Selonsertib targets a novel, nonhemodynamic pathway in CKD. Our data suggest that ASK1 inhibition, when combined with ACEI, has additive effects to reduce progression of glomerulosclerosis, attenuate kidney function decline, and reduce podocyte loss.
10.34067/KID.0001032022
KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression.
JCI insight
Despite recent progress in the identification of mediators of podocyte injury, mechanisms underlying podocyte loss remain poorly understood, and cell-specific therapy is lacking. We previously reported that kidney and brain expressed protein (KIBRA), encoded by WWC1, promotes podocyte injury in vitro through activation of the Hippo signaling pathway. KIBRA expression is increased in the glomeruli of patients with focal segmental glomerulosclerosis, and KIBRA depletion in vivo is protective against acute podocyte injury. Here, we tested the consequences of transgenic podocyte-specific WWC1 expression in immortalized human podocytes and in mice, and we explored the association between glomerular WWC1 expression and glomerular disease progression. We found that KIBRA overexpression in immortalized human podocytes promoted cytoplasmic localization of Yes-associated protein (YAP), induced actin cytoskeletal reorganization, and altered focal adhesion expression and morphology. WWC1-transgenic (KIBRA-overexpressing) mice were more susceptible to acute and chronic glomerular injury, with evidence of YAP inhibition in vivo. Of clinical relevance, glomerular WWC1 expression negatively correlated with renal survival among patients with primary glomerular diseases. These findings highlight the importance of KIBRA/YAP signaling to the regulation of podocyte structural integrity and identify KIBRA-mediated injury as a potential target for podocyte-specific therapy in glomerular disease.
10.1172/jci.insight.165002
The Pathophysiology of HS in Renal Glomerular Diseases.
Biomolecules
Renal glomerular diseases such as glomerulosclerosis and diabetic nephropathy often result in the loss of glomerular function and consequently end-stage renal disease. The glomerulus consists of endothelial cells, mesangial cells and glomerular epithelial cells also referred to as podocytes. A fine-tuned crosstalk between glomerular cells warrants control of growth factor synthesis and of matrix production and degradation, preserving glomerular structure and function. Hydrogen sulfide (HS) belongs together with nitric oxide (NO) and carbon monoxide (CO) to the group of gasotransmitters. During the last three decades, these higher concentration toxic gases have been found to be produced in mammalian cells in a well-coordinated manner. Recently, it became evident that HS and the other gasotransmitters share common targets as signalling devices that trigger mainly protective pathways. In several animal models, HS has been demonstrated as a protective factor in the context of kidney disorders, in particular of diabetic nephropathy. Here, we focus on the synthesis and action of HS in glomerular cells, its beneficial effects in the glomerulus and its action in the context of the other gaseous signalling molecules NO and CO.
10.3390/biom12020207
Deletion of podocyte Rho-associated, coiled-coil-containing protein kinase 2 protects mice from focal segmental glomerulosclerosis.
Communications biology
Focal segmental glomerulosclerosis (FSGS) shares podocyte damage as an essential pathological finding. Several mechanisms underlying podocyte injury have been proposed, but many important questions remain. Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) is a serine/threonine kinase responsible for a wide array of cellular functions. We found that ROCK2 is activated in podocytes of adriamycin (ADR)-induced FSGS mice and cultured podocytes stimulated with ADR. Conditional knockout mice in which the ROCK2 gene was selectively disrupted in podocytes (PR2KO) were resistant to albuminuria, glomerular sclerosis, and podocyte damage induced by ADR injection. In addition, pharmacological intervention for ROCK2 significantly ameliorated podocyte loss and kidney sclerosis in a murine model of FSGS by abrogating profibrotic factors. RNA sequencing of podocytes treated with a ROCK2 inhibitor proved that ROCK2 is a cyclic nucleotide signaling pathway regulator. Our study highlights the potential utility of ROCK2 inhibition as a therapeutic option for FSGS.
10.1038/s42003-024-06127-3
Protective Role of the Podocyte IL-15 / STAT5 Pathway in Focal Segmental Glomerulosclerosis.
Kidney international reports
Introduction:During glomerular diseases, podocyte-specific pathways can modulate the intensity of histological disease and prognosis. The therapeutic targeting of these pathways could thus improve the management and prognosis of kidney diseases. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, classically described in immune cells, has been recently described in detail in intrinsic kidney cells. Methods:We describe STAT5 expression in human kidney biopsies from patients with focal segmental glomerulosclerosis (FSGS) and studied mice with a podocyte-specific deletion in experimental glomerular diseases. Results:Here, we show, for the first time, that STAT5 is activated in human podocytes in FSGS. In addition, podocyte-specific inactivation aggravates the structural and functional alterations in a mouse model of FSGS. This could be due, at least in part, to an inhibition of autophagic flux. Finally, interleukin 15 (IL-15), a classical activator of STAT5 in immune cells, increases STAT5 phosphorylation in human podocytes, and its administration alleviates glomerular injury by maintaining autophagic flux in podocytes. Conclusion:Activating podocyte STAT5 with commercially available IL-15 represents a potential new therapeutic avenue for FSGS.
10.1016/j.ekir.2024.01.010
WIP1 inhibition as a new therapeutic strategy for collapsing glomerulopathy.
Kidney international
Collapsing glomerulopathy (CG) is an aggressive variant of focal and segmental glomerulosclerosis. Understanding the diverse mechanisms that can drive CG promises to uncover new therapeutic strategies. In this issue, Duret et al. identify WIP1 phosphatase as a therapeutic target for CG. Using genetic ablation and pharmacologic inhibition, they show that blockade of WIP1 activity is protective in 2 different mouse models of CG. This study highlights the complex interplay of glomerular signaling pathways in CG and offers hope for targeted therapies.
10.1016/j.kint.2024.02.011