Nephron Research Articles

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND THE DIRECT LINK WITH SYSTEMIC ARTERIAL HYPERTENSION: LITERATURE REVIEW

The human body every minute tries to keep itself in homeostatic balance. The kidneys mediate this regulation by reabsorbing or excreting excess water and the ions present in it. The amount of water removed from the urine is called diuresis. The kidney has anatomy that allows the reabsorption of water in various structures, such as the distal nephron (distal tubule and collecting duct). Furthermore, above the organ, there is the adrenal gland which produces aldosterone, a hormone capable of reabsorbing Na+ in the distal tubules and reabsorbing K+. Low blood pressure secretes aldosterone, which as a result of the pressure drop activates a pathway that releases a hormone that secretes aldosterone to increase pressure, angiotensin II (ANG II). ANG II has vasoactive properties. This hormone triggers the renin-angiotensin system. ANG II functions as a signal that the adrenal cortex should release aldosterone. The process occurs as follows: (a) the juxtaglomerular cells secrete renin; (b) the function of renin will be to transform angiotensinogen (inactive) into active, angiotensin I (ANGI); (c) when the active protein is circulating in the blood, it encounters an angiotensin-converting enzyme (ACE), which it will transform into angiotensin II; (d) ANG II is released into the blood, when it reaches the adrenal gland, stimulates the synthesis and release of aldosterone and, therefore, aldosterone in the distal nephron stimulates the reabsorption of Na+ in the renal tubule.

Role of paraoxonase 3 in regulating ENaC-mediated Na+ transport in the distal nephron.

Paraoxonase 3 (PON3) is expressed in the aldosterone-sensitive distal nephron, where filtered Na+ is reabsorbed mainly via the epithelial Na+ channel (ENaC) and Na+ -coupled co-transporters. We previously showed that PON3 negatively regulates ENaC through a chaperone mechanism. The present study aimed to determine the physiological role of PON3 in renal Na+ and K+ homeostasis. Pon3 knockout (KO) mice had higher amiloride-induced natriuresis and lower plasma [K+ ] at baseline. Single channel recordings in split-open tubules showed that the number of active channels per patch was significantly higher in KO mice, resulting in a higher channel activity in the absence of PON3. Although whole kidney abundance of ENaC subunits was not altered in Pon3 KOs, ENaC gamma subunit was more apically distributed within the connecting tubules and cortical collecting ducts of Pon3 KO kidneys. Additionally, small interfering RNA-mediated knockdown of PON3 in cultured mouse cortical collecting duct cells led to an increased surface abundance of ENaC gamma subunit. As a result of lower plasma [K+ ], sodium chloride co-transporter phosphorylation was enhanced in the KO kidneys, a phenotype that was corrected by a high K+ diet. Finally, PON3 expression was upregulated in mouse kidneys under dietary K+ restriction, potentially providing a mechanism to dampen ENaC activity and associated K+ secretion. Taken together, our results show that PON3has a role in renal Na+ and K+ homeostasis through regulating ENaC functional expression in the distal nephron. KEY POINTS: Paraoxonase 3 (PON3) is expressed in the distal nephron of mouse kidneys and functions as a molecular chaperone to reduce epithelial Na+ channel (ENaC) expression and activity in heterologous expression systems. We examined the physiological role of PON3 in renal Na+ and K+ handling using a Pon3 knockout (KO) mouse model. At baseline, Pon3 KO mice had lower blood [K+ ], more functional ENaC in connecting tubules/cortical collecting ducts, higher amiloride-induced natriuresis, and enhanced sodium chloride co-transporter (NCC) phosphorylation. Upon challenge with a high K+ diet, Pon3 KO mice had normalized blood [K+ ] and -NCC phosphorylation but lower circulating aldosterone levels compared to their littermate controls. Kidney PON3 abundance was altered in mice under dietary K+ loading or K+ restriction, providing a potential mechanism for regulating ENaC functional expression and renal Na+ and K+ homeostasis in the distal nephron.

Dietary sodium alters aldosterone's effect on renal sodium transporter expression and distal convoluted tubule remodelling.

Aldosterone is responsible for maintaining volume and potassium homeostasis. Although high salt consumption should suppress aldosterone production, individuals with hyperaldosteronism lose this regulation, leading to a state of high aldosterone despite dietary sodium consumption. The present study examines the effects of elevated aldosterone, with or without high salt consumption, on the expression of key Na+ transporters and remodelling in the distal nephron. Epithelial sodium channel (ENaC) α-subunit expression was increased with aldosterone regardless of Na+ intake. However, ENaC β- and γ-subunits unexpectedly increased at both a transcript and protein level with aldosterone when high salt was present. Expression of total and phosphorylated Na+ Cl- cotransporter (NCC) significantly increased with aldosterone, in association with decreased blood [K+ ], but the addition of high salt markedly attenuated the aldosterone-dependent NCC increase, despite equally severe hypokalaemia. We hypothesized this was a result of differences in distal convoluted tubule length when salt was given with aldosterone. Imaging and measurement of the entire pNCC-positive tubule revealed that aldosterone alone caused a shortening of this segment, although the tubule had a larger cross-sectional diameter. This was not true when salt was given with aldosterone because the combination was associated with a lengthening of the tubule in addition to increased diameter, suggesting that differences in the pNCC-positive area are not responsible for differences in NCC expression. Together, our results suggest the actions of aldosterone, and the subsequent changes related to hypokalaemia, are altered in the presence of high dietary Na+ . KEY POINTS: Aldosterone regulates volume and potassium homeostasis through effects on transporters in the kidney; its production can be dysregulated, preventing its suppression by high dietary sodium intake. Here, we examined how chronic high sodium consumption affects aldosterone's regulation of sodium transporters in the distal nephron. Our results suggest that high sodium consumption with aldosterone is associated with increased expression of all three epithelial sodium channel subunits, rather than just the alpha subunit. Aldosterone and its associated decrease in blood [K+ ] lead to an increased expression of Na-Cl cotransporter (NCC); the addition of high sodium consumption with aldosterone partially attenuates this NCC expression, despite similarly low blood [K+ ]. Upstream kinase regulators and tubule remodelling do not explain these results.

Demystifying Renal Tubular Disorders in children : A simplified approach

Renal tubular disorders essentially include all disorders of the highly specialized channels of the renal tubular system, from the proximal convoluted tubule to the cortical and medullary collecting ducts. This tubular system is responsible for reabsorption of 99% of glomerular ultrafiltrate, which contains a large amount of fluid (approximately 180 L/day) as well as most electrolytes and many metabolites such as glucose (G), amino acids, bicarbonate (HCO3-), phosphate (PO4 3-), and low-molecular-weight proteins and is essential for maintaining fluid, electrolyte, and acid–base balance. In this review, we will briefly discuss when to suspect a renal tubular disorder, a simplified algorithm for evaluation, and specific mutations of a few common disorders.

Single-cell sequencing dissects the transcriptional identity of activated fibroblasts and identifies novel persistent distal tubular injury patterns in kidney fibrosis

Examining kidney fibrosis is crucial for mechanistic understanding and developing targeted strategies against chronic kidney disease (CKD). Persistent fibroblast activation and tubular epithelial cell (TEC) injury are key CKD contributors. However, cellular and transcriptional landscapes of CKD and specific activated kidney fibroblast clusters remain elusive. Here, we analyzed single cell transcriptomic profiles of two clinically relevant kidney fibrosis models which induced robust kidney parenchymal remodeling. We dissected the molecular and cellular landscapes of kidney stroma and newly identified three distinctive fibroblast clusters with “secretory”, “contractile” and “vascular” transcriptional enrichments. Also, both injuries generated failed repair TECs (frTECs) characterized by decline of mature epithelial markers and elevation of stromal and injury markers. Notably, frTECs shared transcriptional identity with distal nephron segments of the embryonic kidney. Moreover, we identified that both models exhibited robust and previously unrecognized distal spatial pattern of TEC injury, outlined by persistent elevation of renal TEC injury markers including Krt8 and Vcam1, while the surviving proximal tubules (PTs) showed restored transcriptional signature. We also found that long-term kidney injuries activated a prominent nephrogenic signature, including Sox4 and Hox gene elevation, which prevailed in the distal tubular segments. Our findings might advance understanding of and targeted intervention in fibrotic kidney disease.

Gclc as a Marker for Injured Distal Nephron in Ischemia-Reperfusion Induced Acute Kidney Injury.

The distal nephron of kidney plays a pivotal role in advancing acute kidney injury (AKI). Understanding the role of distal nephrons in AKI and identifying markers of injured distal nephrons are critical to comprehending the mechanism of renal injury and identifying novel therapeutic targets. We analyzed single-cell RNA sequencing (scRNA-seq) data from mice with AKI induced by ischemia-reperfusion (IR), unilateral ureteral obstruction (UUO), cisplatin (CP), sodium oxalate (SO) and lipopolysaccharide (LPS). Additionally, we analyzed renal transcriptomics samples for AKI. Subsequently, we validated the effectiveness of targeting the biomarker Gclc in vitro and in vivo through metabolomics and immunofluorescence. The LOH-Inj and DCT-Inj subtypes were identified through scRNA-seq. Compared to normal distal nephrons, the injured distal nephrons exhibited higher levels of ferroptosis, pro-inflammation, and fibrosis. The expression of ferroptosis-related gene Gclc were high in various AKI models. Furthermore, Gclc was exclusively expressed in the distal nephron and upregulated in the injury subtype. To confirm our findings, we suppressed GCLC expression in the kidneys, resulting to aggravated IR-induced AKI. Inhibition of Gclc promoted damage to primarily renal tubular epithelial cells by promoting inflammatory infiltration, inhibiting glutathione metabolism and exacerbating oxidative stress. Our research findings suggest that Gclc is a potential marker for injured distal nephron.

Renal macrophages monitor and remove particles from urine to prevent tubule obstruction

When the filtrate of the glomerulus flows through the renal tubular system, various microscopic sediment particles, including mineral crystals, are generated. Dislodging these particles is critical to ensuring the free flow of filtrate, whereas failure to remove them will result in kidney stone formation and obstruction. However, the underlying mechanism for the clearance is unclear. Here, using high-resolution microscopy, we found that the juxtatubular macrophages in the renal medulla constitutively formed transepithelial protrusions and "sampled" urine contents. They efficiently sequestered and phagocytosed intraluminal sediment particles and occasionally transmigrated to the tubule lumen to escort the excretion of urine particles. Mice with decreased renal macrophage numbers were prone to developing various intratubular sediments, including kidney stones. Mechanistically, the transepithelial behaviors of medulla macrophages required integrin β1-mediated ligation to the tubular epithelium. These findings indicate that medulla macrophages sample urine content and remove intratubular particles to keep the tubular system unobstructed.

Pendrin: linking acid base to blood pressure.

Pendrin (SLC26A4) is an anion exchanger from the SLC26 transporter family which is mutated in human patients affected by Pendred syndrome, an autosomal recessive disease characterized by sensoneurinal deafness and hypothyroidism. Pendrin is also expressed in the kidney where it mediates the exchange of internal HCO3- for external Cl- at the apical surface of renal type B and non-A non-B-intercalated cells. Studies using pendrin knockout mice have first revealed that pendrin is essential for renal base excretion. However, subsequent studies have demonstrated that pendrin also controls chloride absorption by the distal nephron and that this mechanism is critical for renal NaCl balance. Furthermore, pendrin has been shown to control vascular volume and ultimately blood pressure. This review summarizes the current knowledge about how pendrin is linking renal acid-base regulation to blood pressure control.

KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions, and their impairment causes aplasia cutis.

Aplasia cutis congenita (ACC) is a congenital epidermal defect of the midline scalp and has been proposed to be due to a primary keratinocyte abnormality. Why it forms mainly at this anatomic site has remained a long-standing enigma. KCTD1 mutations cause ACC, ectodermal abnormalities, and kidney fibrosis, whereas KCTD15 mutations cause ACC and cardiac outflow tract abnormalities. Here, we found that KCTD1 and KCTD15 can form multimeric complexes and can compensate for each other's loss and that disease mutations are dominant negative, resulting in lack of KCTD1/KCTD15 function. We demonstrated that KCTD15 is critical for cardiac outflow tract development, whereas KCTD1 regulates distal nephron function. Combined inactivation of KCTD1/KCTD15 in keratinocytes resulted in abnormal skin appendages but not in ACC. Instead, KCTD1/KCTD15 inactivation in neural crest cells resulted in ACC linked to midline skull defects, demonstrating that ACC is not caused by a primary defect in keratinocytes but is a secondary consequence of impaired cranial neural crest cells, giving rise to midline cranial suture cells that express keratinocyte-promoting growth factors. Our findings explain the clinical observations in patients with KCTD1 versus KCTD15 mutations, establish KCTD1/KCTD15 complexes as critical regulators of ectodermal and neural crest cell functions, and define ACC as a neurocristopathy.

MicroRNA-19 is regulated by aldosterone in a sex-specific manner to alter kidney sodium transport.

A key regulator of blood pressure homeostasis is the steroid hormone aldosterone, which is released as the final signaling hormone of the renin-angiotensin-aldosterone-signaling (RAAS) system. Aldosterone increases sodium (Na+) reabsorption in the kidney distal nephron to regulate blood volume. Unregulated RAAS signaling can lead to hypertension and cardiovascular disease. The serum and glucocorticoid kinase (SGK1) coordinates much of the Na+ reabsorption in the cortical collecting duct (CCD) tubular epithelial cells. We previously demonstrated that aldosterone alters the expression of microRNAs (miRs) in CCD principal cells. The aldosterone-regulated miRs can modulate Na+ transport and the cellular response to aldosterone signaling. However, the sex-specific regulation of miRs by aldosterone in the kidney distal nephron has not been explored. In this study, we report that miR-19, part of the miR-17-92 cluster, is upregulated in female mouse CCD cells in response to aldosterone activation. Mir-19 binding to the 3'-untranslated region of SGK1 was confirmed using a dual-luciferase reporter assay. Increasing miR-19 expression in CCD cells decreased SGK1 message and protein expression. Removal of this cluster using a nephron-specific, inducible knockout mouse model increased SGK1 expression in female mouse CCD cells. The miR-19-induced decrease in SGK1 protein expression reduced the response to aldosterone stimulation and may account for sex-specific differences in aldosterone signaling. By examining evolution of the miR-17-92 cluster, phylogenetic sequence analysis indicated that this cluster arose at the same time that other Na+-sparing and salt regulatory proteins, specifically SGK1, first emerged, indicating a conserved role for these miRs in kidney function of salt and water homeostasis.NEW & NOTEWORTHY Expression of the microRNA-17-92 cluster is upregulated by aldosterone in mouse cortical collecting duct principal cells, exclusively in female mice. MiR-19 in this cluster targets the serum and glucocorticoid kinase (SGK1) to downregulate both mRNA and protein expression, resulting in a decrease in sodium transport across epithelial cells of the collecting duct. The miR-17-92 cluster is evolutionarily conserved and may act as a novel feedback regulator for aldosterone signaling in females.

Generation of renal tubular organoids from adult SOX9+ kidney progenitor cells.

The pathogenesis of several kidney diseases results in the eventual destruction of the renal tubular system, which can progress to end-stage renal disease. Previous studies have demonstrated the involvement of a population of SOX9-positive cells in kidney regeneration and repair process following kidney injury. However, the ability of these cells to autonomously generate kidney organoids has never been investigated. Here, we isolated SOX9+ kidney progenitor cells (KPCs) from both mice and humans and tested their differentiation potential in vitro. The data showed that the human SOX9+ KPC could self-assemble into organoids with kidney-like morphology. We also used single-cell RNA sequencing to characterize the organoid cell populations and identified four distinct types of renal tubular cells. Compared to the induced pluripotent stem cell-derived kidney organoids, KPC demonstrated more tubular differentiation potential but failed to differentiate into glomerular cells. KPC-derived organoid formation involved the expression of genes related to metanephric development and followed a similar mechanism to renal injury repair in acute kidney injury patients. Altogether, our study provided a potentially useful approach to generating kidney tubular organoids for future application.

TNF- α from the Proximal Nephron Exacerbates Aristolochic Acid Nephropathy.

Aristolochic acid nephropathy (AAN) presents with tubular epithelial cell (TEC) damage and tubulointerstitial inflammation. Although tumor necrosis factor-α (TNF) regulates cell apoptosis and inflammatory responses, the effects of tubular TNF in the progression of AAN require elucidation. Floxed TNF mice on the 129/SvEv background were crossed with PEPCK-Cre mice to generate PEPCK-Cre+TNFflox/flox (TNF PTKO) mice or bred with Ksp-Cre mice to generate KSP-Cre+TNFflox/flox (TNF DNKO) mice. TNF PTKO, TNF DNKO, and WT controls (Cre negative littermates) were subjected to acute and chronic AAN. Deletion of TNF in the proximal but not distal nephron attenuated kidney injury, renal inflammation, and tubulointerstitial fibrosis after acute or chronic aristolochic acid exposure. The TNF PTKO mice did not have altered numbers of infiltrating myeloid cells in AAN kidneys. Nevertheless, kidneys from aristolochic acid-treated TNF PTKO mice had reduced levels of proteins involved in regulated cell death, higher proportions of TECs in the G0/G1 phase, and reduced TEC proportions in the G2/M phase. Pifithrin-α, which restores the cell cycle, abrogated differences between the wild-type and PTKO cohorts in G2/M phase arrest of TECs and kidney fibrosis after aristolochic acid exposure. TNF from the proximal but not the distal nephron propagates kidney injury and fibrogenesis in aristolochic acid nephropathy in part by inducing G2/M cell cycle arrest of TECs.

Mice lacking γENaC palmitoylation sites maintain benzamil-sensitive Na+ transport despite reduced channel activity.

Epithelial Na+ channels (ENaCs) control extracellular fluid volume by facilitating Na+ absorption across transporting epithelia. In vitro studies showed that Cys-palmitoylation of the γENaC subunit is a major regulator of channel activity. We tested whether γ subunit palmitoylation sites are necessary for channel function in vivo by generating mice lacking the palmitoylated cysteines (γC33A,C41A) using CRISPR/Cas9 technology. ENaCs in dissected kidney tubules from γC33A,C41A mice had reduced open probability compared with wild-type (WT) littermates maintained on either standard or Na+-deficient diets. Male mutant mice also had higher aldosterone levels than WT littermates following Na+ restriction. However, γC33A,C41A mice did not have reduced amiloride-sensitive Na+ currents in the distal colon or benzamil-induced natriuresis compared to WT mice. We identified a second, larger conductance cation channel in the distal nephron with biophysical properties distinct from ENaC. The activity of this channel was higher in Na+-restricted γC33A,C41A versus WT mice and was blocked by benzamil, providing a possible compensatory mechanism for reduced prototypic ENaC function. We conclude that γ subunit palmitoylation sites are required for prototypic ENaC activity in vivo but are not necessary for amiloride/benzamil-sensitive Na+ transport in the distal nephron or colon.

Characterizing post-branching nephrogenesis in the neonatal rabbit

Human nephrogenesis ends prior to birth in term infants (34–36 week gestation), with most (60%) nephrons forming in late gestation in two post-branching nephrogenesis (PBN) periods: arcading and lateral branch nephrogenesis. Preterm infants, however, must execute PBN postnatally. Extreme prematurity is associated with low nephron counts. Identifying additional model(s) that undergo PBN postnatally will help support postnatal PBN in preterm infants. The rabbit exhibits longer postnatal nephrogenesis than the mouse but whether it forms nephrons through PBN has not been determined. We performed morphologic and immunohistological assessments of rabbit nephrogenesis from birth (post-conceptual day 31 or 32) to PC49 using H&E and antibodies against SIX1, SIX2, WT1, ZO-1, and JAG1 in the postnatal period. We performed 3D rendering of the nephrogenic niche to assess for PBN, and supplemented the staining with RNAScope to map the expression of Six1, Six2 (nephron progenitors, NPC), and Ret (ureteric bud tip) transcripts to determine the nephrogenic niche postnatal lifespan. Unlike the mouse, rabbit SIX2 disappeared from NPC before SIX1, resembling the human niche. Active nephrogenesis as defined by the presence of SIX1 + naïve NPC/tip population persisted only until PC35–36 (3–5 postnatal days). 3D morphologic assessments of the cortical nephrons identified an elongated tubule with attached glomeruli extending below the UB tip, consistent with PBN arcades, but not with lateral branch nephrogenesis. We conclude that the rabbit shows morphologic and molecular evidence of PBN arcades continuing postnatally for a shorter period than previously thought. The rabbit is the first non-primate expressing SIX1 in the progenitor population. Our findings suggest that studies of arcading in postnatal nephrogenic niche should be performed within the first 5 days of life in the rabbit.

Critical Role of mTORC2 in Maintaining Sodium and Potassium Balance: Implications for Aldosterone-Independent Regulation of Epithelial Sodium Channel (ENaC) in the Distal Nephron

Critical Role of mTORC2 in Maintaining Sodium and Potassium Balance: Implications for Aldosterone-Independent Regulation of Epithelial Sodium Channel (ENaC) in the Distal Nephron

Role of Paraoxonase 3 (PON3) in Regulating Epithelial Sodium Channel (ENaC)-Mediated Na+ Transport in Distal Nephron

Role of Paraoxonase 3 (PON3) in Regulating Epithelial Sodium Channel (ENaC)-Mediated Na+ Transport in Distal Nephron

In Vivo Assessment of Laboratory-Grown Kidney Tissue Grafts.

Directed differentiation of stem cells is an attractive approach to generate kidney tissue for regenerative therapies. Currently, the most informative platform to test the regenerative potential of this tissue is engraftment into kidneys of immunocompromised rodents. Stem cell-derived kidney tissue is vascularized following engraftment, but the connection between epithelial tubules that is critical for urine to pass from the graft to the host collecting system has not yet been demonstrated. We show that one significant obstacle to tubule fusion is the accumulation of fibrillar collagens at the interface between the graft and the host. As a screening strategy to identify factors that can prevent this collagen accumulation, we propose encapsulating laboratory-grown kidney tissue in fibrin hydrogels supplemented with candidate compounds such as recombinant proteins, small molecules, feeder cells, and gene therapy vectors to condition the local graft environment. We demonstrate that the AAV-DJ serotype is an efficient gene therapy vector for the subcapsular region and that it is specific for interstitial cells in this compartment. In addition to the histological evaluation of epithelial tubule fusion, we demonstrate the specificity of two urine biomarker assays that can be used to detect human-specific markers of the proximal nephron (CD59) and the distal nephron (uromodulin), and we demonstrate the deposition of human graft-derived urine into the mouse collecting system. Using the testing platform described in this report, it will be possible to systematically screen factors for their potential to promote epithelial fusion of graft and host tissue with a functional intravital read-out.

Immunohistochemical analysis of renal oxidative damage in senior and geriatric cats with chronic kidney disease

Oxidative stress is a well-known cause of chronic kidney disease (CKD). In this study, renal oxidative damage in azotaemic and non-azotaemic aged cats with naturally occurring CKD was investigated using immunohistochemistry for 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 4-hydroxynonenal (4-HNE) as markers of oxidative tissue damage. Kidneys were obtained from aged (>10 years old) azotaemic (n = 13) and non-azotaemic (n = 7) cats. Immunoreactivity for 8-OHdG was found in the nuclei of glomeruli, proximal and distal tubules, loops of Henle and collecting ducts, whereas 4-HNE-positive signals were detected in the cytoplasm of distal nephrons in azotaemic and non-azotaemic cats. Quantitative analysis did not identify any significant differences between the azotaemic and non-azotaemic groups for any of the parameters examined. These results indicate that renal oxidative damage occurs in the kidneys of aged cats with CKD, regardless of whether they are azotaemic or non-azotaemic, emphasizing the importance of oxidative stress during early-stage CKD in senior and geriatric cats.

Extra-adrenal aldosterone: a mini review focusing on the physiology and pathophysiology of intrarenal aldosterone.

Accumulating evidence has demonstrated the existence of extra-adrenal aldosterone in various tissues, including the brain, heart, vascular, adipocyte, and kidney, mainly based on the detection of the CYP11B2 (aldosterone synthase, cytochrome P450, family 11, subfamily B, polypeptide 2) expression using semi-quantitative methods including reverse transcription-polymerase chain reaction and antibody-based western blotting, as well as local tissue aldosterone levels by antibody-based immunosorbent assays. This mini-review highlights the current evidence and challenges in extra-adrenal aldosterone, focusing on intrarenal aldosterone. A narrative review. Locally synthesized aldosterone may play a vital role in various physio-pathological processes, especially cardiovascular events. The site of local aldosterone synthesis in the kidney may include the mesangial cells, podocytes, proximal tubules, and collecting ducts. The synthesis of renal aldosterone may be regulated by (pro)renin receptor/(pro)renin, angiotensin II/Angiotensin II type 1 receptor, wnt/β-catenin, cyclooxygenase-2/prostaglandin E2, and klotho. Enhanced renal aldosterone release promotes Na+ reabsorption and K+ excretion in the distal nephron and may contribute to the progress of diabetic nephropathy and salt-related hypertension. Inhibition of intrarenal aldosterone signaling by aldosterone synthase inhibitors or mineralocorticoid receptor antagonists may be a hopeful pharmacological technique for the therapy of diabetic nephropathy and saltrelated hypertension. Yet, current reports are often conflicting or ambiguous, leading many to question whether extra-adrenal aldosterone exists, or whether it is of any physiological and pathophysiological significance.

Angiotensin II hypertension along the female rat tubule: predicted impact on coupled transport of Na+ and K.

Chronic infusion of subpressor level of angiotensin II (ANG II) increases the abundance of Na+ transporters along the distal nephron, balanced by suppression of Na+ transporters along the proximal tubule and medullary thick ascending limb (defined as "proximal nephron"), which impacts K+ handling along the entire renal tubule. The objective of this study was to quantitatively assess the impact of chronic ANG II on the renal handling of Na+ and K+ in female rats, using a computational model of the female rat renal tubule. Our results indicate that the downregulation of proximal nephron Na+ reabsorption (TNa), which occurs in response to ANG II-triggered hypertension, involves changes in both transporter abundance and trafficking. Our model suggests that substantial (∼30%) downregulation of active NHE3 in proximal tubule (PT) microvilli is needed to reestablish the Na+ balance at 2 wk of ANG II infusion. The 35% decrease in SGLT2, a known NHE3 regulator, may contribute to this downregulation. Both depression of proximal nephron TNa and stimulation of distal ENaC raise urinary K+ excretion in ANG II-treated females, while K+ loss is slightly mitigated by cortical NKCC2 and NCC upregulation. Our model predicts that K+ excretion may be more significantly limited during ANG II infusion by ROMK inhibition in the distal nephron and/or KCC3 upregulation in the PT, which remain open questions for experimental validation. In summary, our analysis indicates that ANG II hypertension triggers a series of events from distal TNa stimulation followed by compensatory reduction in proximal nephron TNa and accompanying adjustments to limit excessive K+ secretion.NEW & NOTEWORTHY We used a computational model of the renal tubule to assess the impact of 2-wk angiotensin II (ANG II) infusion on the handling of Na+ and K+ in female rats. ANG II strongly stimulates distal Na+ reabsorption and K+ secretion. Simulations indicate that substantial downregulation of proximal tubule NHE3 is needed to reestablish Na+ balance at 2 wk. Proximal adaptations challenge K+ homeostasis, and regulation of distal NCC and specific K+ channels likely limit urinary K+ losses.