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Background Adiponectin is an adipokine that is elevated in kidney disease. Evidence suggests that adiponectin exerts a direct effect on the podocyte and may play a role in the pathogenesis of proteinuria. The objectives of this study were to characterize serum and urine adiponectin levels over time in patients with focal segmental glomerulosclerosis (FSGS) and to evaluate the role of baseline levels of adiponectin as a predictor of clinical remission. Methods This was a study of 60 individuals, ages 3–38 years, with steroid-resistant FSGS enrolled in the FSGS clinical trial. Serial measurements of serum and urine adiponectin were obtained at baseline and 26 and 52 weeks. Results Participants were of mean age 19.4 ± 10.2 years (50 % male, 33 % black). Serum adiponectin (baseline mean 14.3 ± 6.6 μg/ml) and urine adiponectin:creatinine (Uadp/cr) (baseline mean 126.8 ± 178.9 μg/ml) directly correlated with proteinuria at all time points ( r  = 0.37–0.81; all p  < 0.05). Proteinuria, hypoalbuminemia, and hyperlipidemia were significant independent predictors of greater serum adiponectin and Uadp/cr in multivariate analysis. Lower tertiles of baseline serum adiponectin were associated with greater response to treatment at 52 weeks when adjusted for age, sex, body mass index (BMI) z score, and estimated glomerular filtration rate (eGFR) [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.26–0.91, p  = 0.023). For log Uadp/cr, the OR for remission was 0.43 (95 % CI 0.21–0.89, p  = 0.02) at 52 weeks. However, when baseline urine protein:creatinine was added to the models, the relationships were no longer significant. Conclusions Serum and urine adiponectin levels were directly associated with proteinuria and paralleled changes in proteinuria over time in children and young adults with FSGS. Although baseline adiponectin was lower in responders, response to treatment in patients with FSGS was not associated with serum and urine adiponectin levels but, rather, was related to proteinuria.

Autophagy is a conserved lysosomal pathway for the degradation of cytoplasmic components. Basal autophagy in kidney cells is essential for the maintenance of kidney homeostasis, structure and function. Under stress conditions, autophagy is altered as part of the adaptive response of kidney cells, in a process that is tightly regulated by signalling pathways that can modulate the cellular autophagic flux — mammalian target of rapamycin, AMP-activated protein kinase and sirtuins are key regulators of autophagy. Dysregulated autophagy contributes to the pathogenesis of acute kidney injury, to incomplete kidney repair after acute kidney injury and to chronic kidney disease of varied aetiologies, including diabetic kidney disease, focal segmental glomerulosclerosis and polycystic kidney disease. Autophagy also has a role in kidney ageing. However, questions remain about whether autophagy has a protective or a pathological role in kidney fibrosis, and about the precise mechanisms and signalling pathways underlying the autophagy response in different types of kidney cells and across the spectrum of kidney diseases. Further research is needed to gain insights into the regulation of autophagy in the kidneys and to enable the discovery of pathway-specific and kidney-selective therapies for kidney diseases and anti-ageing strategies.In this Review, the authors summarize the basics of autophagy and the signalling pathways involved in its regulation, and examine the multiple roles of autophagy in kidney cells, from its involvement in kidney maintenance and responses to injury, to its potential contribution to glomerular and tubulointerstitial disease.

Using the Nephrotic Syndrome Study Network Consortium data set and other publicly available transcriptomic data sets, we identified retinoic acid receptor responder protein 1 (RARRES1) as a gene whose expression positively correlated with renal function decline in human glomerular disease. The glomerular expression of RARRES1, which is largely restricted to podocytes, increased in focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). TNF-α was a potent inducer of RARRES1 expression in cultured podocytes, and transcriptomic analysis showed the enrichment of cell death pathway genes with RARRES1 overexpression. The overexpression of RARRES1 indeed induced podocyte apoptosis in vitro. Notably, this effect was dependent on its cleavage in the extracellular domain, as the mutation of its cleavage site abolished the apoptotic effect. Mechanistically, the soluble RARRES1 was endocytosed and interacted with and inhibited RIO kinase 1 (RIOK1), resulting in p53 activation and podocyte apoptosis. In mice, podocyte-specific overexpression of RARRES1 resulted in marked glomerular injury and albuminuria, while the overexpression of RARRES1 cleavage mutant had no effect. Conversely, podocyte-specific knockdown of Rarres1 in mice ameliorated glomerular injury in the setting of adriamycin-induced nephropathy. Our study demonstrates an important role and the mechanism of RARRES1 in podocyte injury in glomerular disease.

Ectopic lipid deposition, mitochondrial injury, and inflammatory responses contribute to the development of diabetic kidney disease (DKD); however, the mechanistic link between these processes remains unclear. In this study, we demonstrate that the ceramide synthase 6 (CerS6) is primarily localized in podocytes of the glomeruli and is upregulated in two different models of diabetic mice. Podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammatory responses in male diabetic mice and in male mice with adriamycin-induced nephropathy. In contrast, podocyte-specific overexpression of CerS6 sufficiently induces proteinuria. Mechanistically, CerS6-derived ceramide (d18:1/16:0) can bind to the mitochondrial channel protein VDAC1 at Glu59 residue, initiating mitochondrial DNA (mtDNA) leakage, activating the cGAS-STING signaling pathway, and ultimately promoting an immune-inflammatory response in the kidney. Importantly, CERS6 expression is increased in podocytes from kidney biopsies of patients with DKD and focal segmental glomerulosclerosis (FSGS), and the expression level of CERS6 is correlated negatively with glomerular filtration rate and positively with proteinuria. Thus, our findings suggest that targeting CerS6 may be a potential therapeutic strategy for proteinuric kidney diseases. Disturbed lipid metabolism is a feature of diabetic kidney disease (DKD). Here the authors report that ceramide synthase 6 (CerS6) in podocytes contributes to the pathogenesis of diabetic kidney disease (DKD) in male mice by inducing mitochondrial DNA leakage, activating the cGAS-STING pathway and promoting inflammation.

Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-β signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.

With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence-associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti-PD-1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti-PD-1 antibody treatment improved the health span of podocytes. Administering the same anti-PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS.

Podocyte injury plays a central role in both focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). Pathogenic mechanisms are diverse and incompletely understood, partially overlap between FSGS and MCD, and are not reflected by kidney biopsy. In order to optimize the current variable response to treatment, personalized management should rely on pathogenesis. One promising approach involves identifying biomarkers associated with specific pathogenic pathways. With the advancement of technology, proteomic studies could be a valuable tool to improve knowledge in this area and define valid biomarkers, as they have in other areas of glomerular disease. This work attempts to cover and discuss the main mechanisms of podocyte injury, followed by a review of the recent literature on proteomic biomarker studies in podocytopathies. Most of these studies have been conducted on biofluids, while tissue proteomic studies applied to podocytopathies remain limited. While we recognize the importance of non-invasive biofluid biomarkers, we propose a sequential approach for their development: tissue proteomics could first identify proteins with increased expression that may reflect underlying disease mechanisms; subsequently, the validation of these proteins in urine or plasma could pave the way to a diagnostic and prognostic biomarker-based approach.

Formins are proteins that catalyze the formation of linear filaments made of actin. INF2, a formin, is crucial for correct vesicular transport, microtubule stability and mitochondrial division. Its activity is regulated by a complex of cyclase-associated protein and lysine-acetylated G-actin (KAc-actin), which helps INF2 adopt an inactive conformation through the association of its N-terminal diaphanous inhibitory domain (DID) with its C-terminal diaphanous autoinhibitory domain. INF2 activation can occur through calmodulin binding, KAc-actin deacetylation, G-actin binding, or association with the Cdc42 GTPase. Mutations in the INF2 DID are linked to focal segmental glomerulosclerosis (FSGS), affecting podocytes, and Charcot-Marie-Tooth disease, which affects Schwann cells and leads to axonal loss. At least 80 pathogenic DID variants of INF2 have been identified, with potential for many more. These mutations disrupt INF2 regulation, leading to excessive actin polymerization. This in turn causes altered intracellular trafficking, abnormal mitochondrial dynamics, and profound transcriptional reprogramming via the MRTF/SRF complex, resulting in mitotic abnormalities and p53-mediated cell death. This sequence of events could be responsible for progressive podocyte loss during glomerular degeneration in FSGS patients. Pharmacological targeting of INF2 or actin polymerization could offer the therapeutic potential to halt the progression of FSGS and improve outcomes for patients with INF2-linked disease.

Podocytes form the outer part of the glomerular filter, where they have to withstand enormous transcapillary filtration forces driving glomerular filtration. Detachment of podocytes from the glomerular basement membrane precedes most glomerular diseases. However, little is known about the regulation of podocyte adhesion in vivo. Thus, we systematically screened for podocyte-specific focal adhesome (FA) components, using genetic reporter models in combination with iTRAQ-based mass spectrometry. This approach led to the identification of FERM domain protein EPB41L5 as a highly enriched podocyte-specific FA component in vivo. Genetic deletion of Epb41l5 resulted in severe proteinuria, detachment of podocytes, and development of focal segmental glomerulosclerosis. Remarkably, by binding and recruiting the RhoGEF ARGHEF18 to the leading edge, EPB41L5 directly controls actomyosin contractility and subsequent maturation of focal adhesions, cell spreading, and migration. Furthermore, EPB41L5 controls matrix-dependent outside-in signaling by regulating the focal adhesome composition. Thus, by linking extracellular matrix sensing and signaling, focal adhesion maturation, and actomyosin activation EPB41L5 ensures the mechanical stability required for podocytes at the kidney filtration barrier. Finally, a diminution of EPB41L5-dependent signaling programs appears to be a common theme of podocyte disease, and therefore offers unexpected interventional therapeutic strategies to prevent podocyte loss and kidney disease progression.