American journal of physiology. Renal physiology最新文献

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) and remains a significant clinical challenge due to its complex pathogenesis. This review explores the intricate interplay of metabolic, inflammatory, and cellular mechanisms that drive DKD progression, with a particular focus on lipid metabolism, mitochondrial dysfunction, oxidative stress, inflammation, cell injury, and epigenetic modifications. Advances in histopathological and molecular studies have expanded our understanding of glomerular, tubular, and vascular abnormalities in DKD, highlighting the critical role of nuclear hormone receptors, transcription factors, and G protein-coupled receptors in regulating renal lipid accumulation, mitochondrial function, inflammation, oxidative stress, and fibrotic pathways. In addition, emerging evidence implicates novel cell death mechanisms, including ferroptosis, necroptosis, pyroptosis, and PANoptosis, in DKD pathology. Epigenetic modifications, including DNA methylation, histone modifications, and noncoding RNAs, further contribute to disease progression by regulating gene expression in response to metabolic stress. As current therapeutic strategies remain insufficient to prevent DKD progression, this review also discusses novel molecular targets and emerging therapeutic approaches aimed at mitigating lipid toxicity, enhancing mitochondrial function, and suppressing inflammation. By integrating insights from histopathology, molecular biology, and translational research, this review provides a comprehensive framework for developing future strategies to delay or prevent DKD progression.

Kidney stone disease is characterized by hypercalciuria and intestinal hyperabsorption of calcium, leading to the formation of calcium crystals in the kidney. Claudin-2 is a tight junction protein that forms paracellular cation pores, and mutations in its gene are associated with kidney stone disease. We have recently shown that mice deficient in Cldn2 are hypercalciuric due to both decreased renal reabsorption and increased intestinal absorption of calcium and develop medullary mineral deposits reminiscent of kidney stone formers. Therefore, we hypothesized that intestinal claudin-2 is important for calcium secretion and that loss of claudin-2 results in increased net intestinal calcium absorption, thereby contributing to kidney stone disease. To test this, we generated intestine-specific Cldn2 knockout mice using a villin-Cre promoter. Female mice showed Cldn2 deletion only in the intestine; however, male mice showed partial deletion of Cldn2 in kidneys. Ileal and colonic calcium permeability were significantly reduced in knockout animals of both sexes. Knockout animals developed transient hypercalciuria (more severe in males than females) at weaning, which was normalized by 4 wk of age. In metabolic balance studies, there was no change in net calcium absorption and in whole body calcium balance in knockout mice of either sex on normal or high-calcium diet, with the exception that males were in slightly positive calcium balance on normal-calcium diet. Our results show that claudin-2 contributes to intestinal permeability to calcium but does not play a significant role in net intestinal calcium absorption or secretion.NEW & NOTEWORTHY Global claudin-2 knockout mice have hypercalciuria due to both intestinal overabsorption of calcium and a renal calcium leak. Here, we generated intestine-specific claudin-2 knockout mice. Ileal and colonic calcium permeability were reduced, but surprisingly these animals exhibited only transient hypercalciuria for 1 wk after weaning. Thus, claudin-2 contributes to intestinal permeability to calcium but does not play a significant role in intestinal calcium absorption or secretion.

Focal segmental glomerulosclerosis (FSGS) is a common glomerular pathology characterized by podocyte injury, which can lead to kidney failure. Among the factors contributing to podocyte damage are mutations in nuclear pore complexes (NPCs), which regulate nuclear-cytoplasmic transport of proteins and RNAs. Defective NPCs can accumulate in highly differentiated, nondividing cells such as podocytes. However, their role in podocyte dysfunction is largely unexplored, particularly as a potential therapeutic target. To address this, we investigated the effects of selinexor (KPT-330), a drug that inhibits XPO1-mediated nuclear-cytoplasmic protein export. In HeLa cells, KPT-330 restored compromised NPC function. Munich Wistar Fröemter (MWF) rats, a model for spontaneous FSGS development, aged 10 wk, were treated with KPT-330 for 10 wk and then observed for another 20 wk. Improvements in kidney function were observed at the end of the 10-wk treatment period, with serum creatinine significantly lower in the KPT-330 group (34.11 ± 1.77 μmol/L) versus the vehicle group (39.25 ± 3.54 μmol/L, P < 0.01). Serum cystatin C levels remained lower in the KPT-330 group (3.62 ± 0.39 μg/mL) versus vehicle (4.19 ± 0.44 μg/mL, P < 0.05) after an additional 20 wk without treatment. Hyperlipidemia was significantly reduced immediately after the end of the 10-wk KPT-330 treatment compared with vehicle (triglyceride: 1.23 ± 0.34 mmol/L vs. 1.92 ± 0.4 mmol/L, P < 0.01; total cholesterol: 1.47 ± 0.08 mmol/L vs. 2.96 ± 0.44 mmol/L, P < 0.0001). However, histopathological parameters, including glomerulosclerosis, podocyte numbers, and activation of parietal epithelial cells, showed that kidney damage continued to progress. Thus, KPT-330 has beneficial effects on kidney function, but was not sufficient to halt the histological progression of glomerular damage.NEW & NOTEWORTHY Focal segmental glomerulosclerosis (FSGS) involves podocyte injury, potentially linked to dysfunctional nuclear pore complexes (NPCs). We show that selinexor (KPT-330), a nuclear export inhibitor, restores NPC function in vitro. In an FSGS rat model, selinexor improves kidney function, lowers serum creatinine and cystatin C levels, and reduces serum lipid levels. However, histological damage persists, indicating partial but not complete protection. These findings highlight NPC-targeted therapies as a potential strategy for treating FSGS.

The arteriovenous fistula (AVF) is the gold standard for hemodialysis vascular access, although inadequate vascular remodeling and intimal hyperplasia pose a major limitation. It is essential to study this in a clinically relevant model. We used an autosomal dominant polycystic kidney disease (ADPKD) model, the most common hereditary cause of chronic kidney disease (CKD), to study the effect of CKD on AVFs. Jugular-carotid AVFs were created in adult B6OlaPkd1^nl/nl (ADPKD) mice and B6OlaPkd1^+/+ littermates. AVFs were harvested 7 days postsurgery for bulk mRNA sequencing or 3 wk postsurgery for histological analysis. We performed weekly AVF flow measurements using Doppler ultrasound and assessed kidney morphology and function by histology and blood urea analysis. Blood pressure was measured using a tail cuff, before and 6 days after AVF surgery. Longitudinal flow data was analyzed using mixed-effects model, histological data using the Mann-Whitney U test. Pkd1^nl/nl mice developed cystic kidneys and elevated blood urea levels (8.7 ± 2.8 mmol/L vs. 24.0 ± 3.8 mmol/L) and higher mean arterial blood pressure (92 vs. 113). AVF flow in Pkd1^nl/nl mice was consistently higher post-AVF creation (1.9-fold difference, P < 0.001), with a 50% reduction in intimal hyperplasia and 30% increase in luminal AVF volume. RNA sequencing showed altered regulation of extracellular matrix in the venous ADPKD AVF, with reduced collagen deposition in the venous outflow tract. The arterial AVF wall had disruption of the elastic laminae. Pkd1^nl/nl mice are a suitable model to study AVF remodeling in a CKD setting, resulting in enhanced luminal volume and higher AVF flow when compared with normotensive mice with normal kidney function.NEW & NOTEWORTHY This work explores the impact of chronic kidney disease (CKD) on arteriovenous fistula (AVF) remodeling using an autosomal dominant polycystic kidney disease (ADPKD) mouse model. Our findings reveal that ADPKD enhances AVF flow and luminal volume while reducing intimal hyperplasia, due to altered extracellular matrix deposition, offering new insights into the vascular AVF changes in a CKD setting. This study highlights the suitability of the ADPKD model for investigating AVF remodeling in a CKD context.

Diabetic nephropathy (DN) is a multifactorial disease in which inflammation and angiogenesis play a crucial role. SerpinE2, or protease nexin-1 (PN-1), is a protease inhibitor of the serpin family, expressed by vascular and inflammatory cells. In this study, we addressed the role of SerpinE2 in DN, using the models of streptozotocin-induced type-1 and db/db type-2 diabetes. Our results indicated that SerpinE2^-/- diabetic mice presented histological features of an aggravated nephropathy compared with wild-type (WT) mice, with higher hypertrophy of glomeruli, greater collagen IV accumulation, and reduced nephrin expression. Moreover, renal function was worsened in SerpinE2^-/- diabetic mice with urine albumin-to-creatinine ratio much higher compared with WT. Consistent with the previously demonstrated antiangiogenic properties of SerpinE2, we observed that glomerular vascularization was higher in SerpinE2^-/- than in WT diabetic mice in early type-1 diabetes, associated with increased proliferation of glomerular cells. Accordingly, renal blood flow reduction in response to diabetes was lower in SerpinE2^-/- mice than in WT mice. In addition, we measured higher mRNA levels of inflammatory cytokines and of midkine in the kidneys of diabetic SerpinE2^-/- mice compared with WT mice. Altogether, our results indicate that SerpinE2 may play a protective role in the development of DN by limiting glomerular damage throughout regulation of early process in angiogenesis and inflammation.NEW & NOTEWORTHY In two different models of diabetes, SerpinE2 deficiency exacerbated nephropathy, as evidenced by increased glomerular hypertrophy and collagen expression, reduced nephrin, and impaired kidney function. Increased angiogenesis and upregulated cytokines were involved. This study is the first to demonstrate a role of SerpinE2 in DN progression by modulating early disease mechanisms.

Acute kidney injury (AKI) is a major clinical concern with limited therapeutic strategies, often leading to chronic kidney disease (CKD) and long-term morbidity. Mitochondrial dysfunction is a major causative factor for AKI onset and progression to CKD. Interventions that restore mitochondrial integrity and cellular energy represent promising therapeutic strategies. This study investigated the potential therapeutic role of MARY1, a novel, potent, and subtype-selective serotonin-2B receptor (5-HT_2BR) antagonist, following ischemia/reperfusion (I/R)-induced AKI in mice and rats. We previously demonstrated that MARY1 induces renal mitochondrial biogenesis (MB), the generation of new functional mitochondria, in vivo. MARY1 (0.3 mg/kg, i.p., daily) administration for 6 days following AKI improves renal function, restores mitochondrial homeostasis and renal vascular integrity, upregulates β-oxidation, and restores genes associated with proximal tubule repair. Moreover, daily treatment with MARY1 for 12 days following AKI restores mitochondrial homeostasis and increases autophagic activity in the renal cortex of mice. These findings establish MARY1-mediated 5-HT_2BR antagonism as a mitochondria-targeted therapeutic strategy that addresses multiple hallmarks of AKI, and as a potential intervention for mitochondrial dysfunction-associated renal diseases.NEW & NOTEWORTHY This study identifies MARY1, a subtype selective 5-HT_2B receptor antagonist, as a novel mitochondria-targeted therapeutic for AKI. MARY1 restores mitochondrial homeostasis, enhances renal vascular integrity, and promotes autophagy and β-oxidation following bilateral I/R injury-induced AKI, leading to improved renal recovery in vivo. These findings highlight a novel therapeutic strategy to mitigate AKI progression and mitochondrial dysfunction.

The distal convoluted tubule (DCT) plays a crucial role in potassium (K⁺) homeostasis, with electrogenic basolateral K⁺ flux well established as a regulator of its function. Although the involvement of electroneutral basolateral K⁺ transport has been hypothesized, its precise role remains unclear. The electroneutral potassium chloride (Cl^-) cotransporter, KCC3, is expressed in the kidney, but its role in DCT function has yet to be fully defined. To explore this, we generated a novel animal model with DCT-specific deletion of KCC3. Our results show that KCC3 deletion in DCT cells led to reduced levels of both total and phosphorylated sodium (Na⁺) Cl^- cotransporter (NCC), along with decreased NCC mRNA expression, indicating a regulatory role for KCC3 in NCC expression at the transcript level. Despite these changes, knockout animals maintained normal electrolyte balance under standard dietary conditions. In response to dietary K⁺ restriction, knockout mice showed no significant differences compared with controls-blood K⁺ levels, NCC phosphorylation, and with no lysine kinase (WNK) body formation in the DCT remained unchanged. These findings suggest that KCC3 is involved in the basal regulation of NCC expression but is not essential for DCT adaptation to K⁺ depletion or for overall K⁺ homeostasis.NEW & NOTEWORTHY Deletion of KCC3 specifically in distal convoluted tubule cells leads to decreased NCC mRNA transcript abundance as well as a reduction in both total and phosphorylated NCC protein levels. Despite these molecular changes, DCT-specific KCC3 deletion does not disrupt overall potassium homeostasis under either standard or low potassium dietary conditions. These findings suggest that other KCC isoforms, such as KCC4, may be involved in regulating the DCT response to reduced dietary potassium intake.

Acute kidney injury (AKI) is a life-threatening condition with high morbidity and mortality, characterized by inflammation linked to organelle stress. Despite its clinical significance, effective therapies remain limited. Although organelle dysfunction is recognized as a driver of inflammation in AKI, the role of interorganelle communication in this process remains poorly understood. PDZ domain-containing 8 (PDZD8), a tethering protein on the endoplasmic reticulum (ER), facilitates ER-endolysosome contact that is essential for endolysosomal maturation. The mature endolysosome is a prerequisite for activating the DNA-sensing innate immune receptor, Toll-like receptor 9 (TLR9). Here, we investigated the role of PDZD8 in the TLR9-NF-κB pathway during AKI using Pdzd8 knockout (KO) mice and in vitro knockdown in human proximal tubular cells (PTCs). Pdzd8 KO mice showed reduced severity of cisplatin-induced AKI and reduced activation of the NF-κB pathway. Mechanistically, PDZD8 knockdown in PTCs impaired endolysosomal maturation and acidification. This functional disruption impeded the proper translocation of TLR9 to endolysosomes, thereby inhibiting the signaling cascade leading to NF-κB activation. Notably, PDZD8 knockdown did not alter mitochondrial morphology or the cytosolic leakage of mitochondrial DNA, an endogenous ligand for TLR9. These findings indicate that PDZD8 is crucial for maintaining endolysosomal homeostasis and regulating the TLR9-NF-κB pathway in cisplatin-induced tubular injury.NEW & NOTEWORTHY This study reveals the critical role of PDZD8 in maintaining endolysosomal homeostasis and regulating the TLR9-NF-κB inflammatory pathway in cisplatin-induced acute kidney injury (AKI). Loss of PDZD8 impaired endolysosomal function, suppressing TLR9 activation and downstream inflammation, leading to reduced tubular damage.

We previously reported that Na⁺-deprived mice lacking CAP1/Prss8 in kidney tubules maintained epithelial sodium channel-mediated sodium balance albeit persistent hypoaldosteronism, hence indicating an uncoupling from aldosterone production. This further suggested an implication of the serine protease CAP1/Prss8 (prostasin) in the cross talk of the kidney with the adrenal gland that does not express prostasin. When these knockout (Ko) mice were additionally exposed to a high K⁺ diet, plasma K⁺ levels and plasma aldosterone concentrations were normalized and no longer different from those of the control mice. The mRNA transcript expression of the adrenal aldosterone synthase Cyp11b2, which was lower in Na⁺-deprived CAP1/Prss8 Ko animals, was in the normal range. Plasma aldosterone levels were similar to control animals, indicating that K⁺ rescued the hypoaldosteronism in Na⁺-deprived CAP1/Prss8 Ko animals. These data suggest that CAP1/Prss8 (prostasin) is implicated in the regulation of aldosterone synthesis or production and that the consequences of CAP1/Prss8 deficiency can be compensated by high dietary K⁺ supplementation. Prostasin may therefore present a promising regulator of aldosterone production by affecting the adrenal steroidogenic pathway.NEW & NOTEWORTHY We explore the role of the serine protease CAP1/Prss8 in aldosterone synthesis. Described previously as a candidate gene for hypertension, the mechanism by which renal serine protease deficiency is implicated in aldosterone production is still largely unknown. Our findings underscore a role of prostasin in the regulation of aldosterone synthesis. In kidney-specific CAP1/Prss8 knockout mice, K⁺ supplementation is predominant over Na⁺ and restores normal aldosterone production proposing new pathways to treat hypo- or hypertension.