The inhibition of renal SGLT2 glucose reabsorption has proven its therapeutic efficacy in chronic kidney disease. SGLT2 inhibitors (SGLTi) have been intensively studied in rodent models to identify the mechanisms of SGLT2i-mediated nephroprotection. So far, the overwhelming effects from clinical trials, could only partially be reproduced in rodent models of renal injury. However, a commonly disregarded observation from these studies, is the increase in kidney weight after SGLT2i administration. Increased kidney mass often relies on tubular growth in response to reabsorption overload during glomerular hyperfiltration. Since SGLT2i suppress hyperfiltration but concomitantly increase renal weight, it seems likely that SGLT2i have a growth promoting effect on the kidney itself, independent of GFR control. This study aimed to investigate the effect of SGLT2i on kidney growth in wildtype animals, to identify enlarged nephron segments and classify the size increase as hypertrophic/hyperplastic growth or cell swelling. SGLT2i empagliflozin increased kidney weight in wildtype mice by 13% compared to controls, while bodyweight and other organs were not affected. The enlarged nephron segments were identified as SGLT2-negative distal segments of proximal tubules and as collecting ducts by histological quantification of tubular cell area. In both segments protein/DNA ratio, a marker for hypertrophic growth, was increased by 6% and 12% respectively, while tubular nuclei number (hyperplasia) was unchanged by empagliflozin. SGLT2-inhibition in early proximal tubules induces a shift of NaCl resorption along the nephron causing compensatory NaCl and H2O reabsorption and presumably cell growth in downstream segments. Consistently, in collecting ducts of empagliflozin-treated mice, mRNA expression of the Na+-channel ENaC and the H2O-channels Aqp-2/Aqp-3 were increased. In addition, the hypoxia marker Hif1α was found increased in intercalated cells of the collecting duct together with evidence for increased proton secretion, as indicated by upregulation of carbonic anhydrases and acidified urine pH in empagliflozin-treated animals. In summary, these data show that SGLT2i induce cell enlargement by hypertrophic growth and possibly cell swelling in healthy kidneys, probably as a result of compensatory glucose, NaCl and H2O hyperreabsorption of SGLT2-negative segments. Particularly affected are the SGLT2-negative proximal tubules (S3) and the collecting duct, areas of low O2 availability.

Organomegaly can be a strong predictor of an underlying pathological condition. There are many standard tables available in various texts listing the normal organ weight range, yet there is a lack of a standard table that is accepted globally. The main reason behind this is variation in organ weight due to socioeconomic status, geographical variation, and racial and stature variation among different global populations. The Western population has different stature compared to our population, that is, residents of Uttarakhand, India. Different studies tabulated organ weights in different regions of the world and correlated with different bodily parameters such as sex, race, stature, BMI, etc, which have shown a significant variation. There are different sets of data available that cannot be accepted universally due to regional variation. Most of the studies done in various parts of the world do not specify the condition of the organ, whether it was normal at the time of study or not. The methods of dissection of organs were also not explained in different studies. In this study, a total of eight organs were weighed from 137 autopsies conducted at the mortuary of the All India Institute of Medical Sciences Rishikesh over a period of 1.5 years. It was found that the average brain weighed in males was 1313.2 gm (±127.7 gm) and among females, it was 1218.0 gm (±122.82 gm). The weight of the heart was 310.1 gm (±83.97 gm) in males and 241.2 gm (±71.42 gm) in females. Right and left lungs weighed 499.4 gm (±207.5 gm)/407.5 gm (±128.66 gm) and 459.6 gm (±179.19 gm)/369.4 gm (±144.17 gm) among males and females, respectively. The liver weight was 1477.0 gm (±370.52 gm) in males and 1309.0 gm (±274.18 gm) among females. Spleen weighed 154.0 gm (±74.63 gm) in males and 156.0 gm (±65.0 gm) in females. The right and left kidneys weighed 125.9 gm (±37.92 gm)/108.1 gm (±28.80 gm) and 126.3 gm (±31.26 gm)/106.6 gm (±22.4 gm) among males and females, respectively. In our study, we have done a histological examination to rule out any pathological condition before including the weight of the organs in the study. The present study is to derive a standard organ weight among the inhabitants of Uttarakhand, India, and to look for a variation in organ weight among different studies done in the past in different regions of the world.

Hydrogen sulfide (H2S), carbon monoxide (CO) and nitric oxide (NO) share signaling and vasorelaxant properties and are involved in proliferation and apoptosis. Inhibiting NO production or availability induces hypertension and proteinuria, which is prevented by concomitant blockade of the H2S producing enzyme cystathionine γ-lyase (CSE) by d,l-propargylglycine (PAG). We hypothesized that blocking H2S production ameliorates Angiotensin II (AngII)-induced hypertension and renal injury in a rodent model. Effects of concomitant administration of PAG or saline were therefore studied in healthy (CON) and AngII hypertensive rats. In CON rats, PAG did not affect systolic blood pressure (SBP), but slightly increased proteinuria. In AngII rats PAG reduced SBP, proteinuria and plasma creatinine (180 ± 12 vs. 211 ± 19 mmHg; 66 ± 35 vs. 346 ± 92 mg/24 h; 24 ± 6 vs. 47 ± 15 μmol/L, respectively; p < 0.01). Unexpectedly, kidney to body weight ratio was increased in all groups by PAG (p < 0.05). Renal injury induced by AngII was reduced by PAG (p < 0.001). HO-1 gene expression was increased by PAG alone (p < 0.05). PAG increased inner cortical tubular cell proliferation after 1 week and decreased outer cortical tubular nucleus number/field after 4 weeks. In vitro proximal tubular cell size increased after exposure to PAG. In summary, blocking H2S production with PAG reduced SBP and renal injury in AngII infused rats. Independent of the cardiovascular and renal effects, PAG increased HO-1 gene expression and kidney weight. PAG alone increased tubular cell size and proliferation in-vivo and in-vitro. Our results are indicative of a complex interplay of gasotransmitter signaling/action of mutually compensatory nature in the kidney.

BACKGROUND: Transforming growth factor (TGF)-β1/Smad signaling pathway plays a critical role in the prolonged glomerulosclerosis (GS), which is an important determinant during the progression in chronic kidney disease (CKD). For recent 30 years, multi-glycoside of Tripterygium wilfordii Hook. f. (GTW), an extract from Chinese herbal medicine has been proved clinically effective in improving GS in CKD in China. However, therapeutic mechanisms involved in vivo are still unclear. In this study, we aimed to explain the dose-effects and molecular mechanisms of GTW on GS by regulating TGF-β1/Smad signaling activity in adriamycin (ADR)-induced nephropathy (ADRN).
METHODS: Rats with ADRN, created by unilateral nephrectomy and twice adriamycin injections (ADR, 4 mg/kg and 2 mg/kg) within 4 weeks, were divided into four groups, the Sham group, the Vehicle group, the low-dose GTW-treated group, and the high-dose GTW-treated group, and that, sacrificed at the end of the 6th week after administration. Proteinuria, blood biochemical parameters, glomerulosclerotic morphological makers, podocyte shape, and nephrin expression were examined, respectively. Protein expressions of key signaling molecules in TGF-β1/Smad pathway, such as TGF-β1, Smad3, phosphorylated-Smad2/3 (p-Smad2/3), and Smad7, were also evaluated individually.
RESULTS: The results indicated that the characterizations of ADRN involved the typical prolonged GS, a small amount of abnormal proteinuria, and the failing renal function; TGF-β1/Smad signaling molecules, especially Smad3, p-Smad2/3, and Smad7 were activated in vivo, accompanied by the exasperation of glomerulosclerotic lesion; GTW at high-dose (100 mg/kg) and low-dose (50 mg/kg) could slightly ameliorate the prolonged GS and nephrin expression, furthermore, the anti-proliferative action of GTW at high-dose was superior to that at low-dose, but caused the significant liver injury; in ADRN model rats, protein expressions of TGF-β1, p-Smad2/3, and Smad7 in the kidneys could be regulated with the treatment of GTW at low-dose.
CONCLUSIONS: This study farther demonstrated that the low-dose of GTW, as a natural regulator in vivo, could effectively and safely ameliorate the prolonged GS in FSGS model, via the potential molecular mechanisms involving the reduction of ECM components and the suppression of TGF-β1 over-expression, as well as the bidirectional regulation of TGF-β1/Smad signaling activity.

BACKGROUND: Cisplatin (cis-diamminedichloroplatinum II; CP) is used widely as an antitumor drug in clinics, but is accompanied with renal toxicity. Cisplatin induced nephrotoxicity consists of change in kidney weight, histological changes in kidney and increase in serum creatinine (Cr) and blood urea nitrogen (BUN). This study was designed to find out a model for prediction of cisplatin induced nephrotoxicity.
METHODS: Pathological damage score, kidney weight, BUN, and Cr of 227 rats that were involved in different projects were determined. A total of 187 rats were treated with 7 mg/kg cisplatin and sacrificed 1 week later.
RESULTS: There was a good significant correlation between normalized kidney weight and logarithmic scale of BUN and Cr. Relationship between BUN, Cr or normalized kidney weight and pathology damage score was significant.
CONCLUSIONS: Normalized kidney weight and pathology damage score is a good predictor of renal function in cisplatin induced nephrotoxicity in experimental rats.

Breviscapine is a flavonoid extracted from a Chinese herb Erigeron breviscapus, previously it was shown that treatment with breviscapine attenuated renal injury in the diabetic rats. The purpose of this study was to investigate whether breviscapine combined with enalapril (an ACE inhibitor) have superior renoprotective effects against diabetic nephropathy. Rats were randomly separated into five groups: control, diabetes, diabetes treated with enalapril, diabetes treated with breviscapine, or diabetes treated with combined enalapril with breviscapine. Twenty-four hours urinary AER and the levels of 3-NT in renal tissue and MDA in renal tissue and urine as well as activities and expression of PKC in renal tissue were determined, and renal tissue morphology were observed by light microscopy after 8 weeks. Expression of TGFβ1 protein was performed by immunohistochemistry method. Increased AER and kidney pathologic injury were attenuated by treatment with either enalapril or breviscapine and further reduced by the combination of the two. Elevated 3-NT in renal tissue and MDA levels in renal tissue and urine were reduced by enalapril or breviscapine and, more effectively, by combined enalapril with breviscapine. PKC activities and expression were higher in renal tissue in diabetic rats than those of the control group, which were reduced by both monotherapies, and further abrogated by combination therapy in both cases. Overexpression of TGFβ1 protein observed in the glomeruli and tubulointerstitium of diabetic rats was attenuated by enalapril or breviscapine to a similar lever and further reduced by the combination of the two. The combination of enalapril and breviscapine confers superiority over monotherapies on renoprotection, which mechanism may be at least partly correlated with synergetic suppression on increased oxidative stress and PKC activities as well as overexpression of TGFβ1 in renal tissue.