American journal of kidney diseases : AJKD : the official journal of the National Kidney Foundation.

1P-0149 Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy

Type 2 diabetes is a metabolic, chronic disorder characterized by insulin resistance and elevated blood glucose levels. Although a large drug portfolio exists to keep the blood glucose levels under control, these medications are not without side effects. More importantly, once diagnosed diabetes is rarely reversible. Dysfunctions in the kidney, retina, cardiovascular system, neurons, and liver represent the common complications of diabetes, which again lack effective therapies that can reverse organ injury. Overall, the molecular mechanisms of how type 2 diabetes develops and leads to irreparable organ damage remain elusive. This review particularly focuses on novel targets that may play role in pathogenesis of type 2 diabetes. Further research on these targets may eventually pave the way to novel therapies for the treatment-or even the prevention-of type 2 diabetes along with its complications.

Emerging Targets in Type 2 Diabetes and Diabetic Complications.

Renal fibrosis is the final, common pathway of end-stage renal disease. Whether and how autophagy contributes to renal fibrosis remains unclear. Here we first detected persistent autophagy in kidney proximal tubules in the renal fibrosis model of unilateral ureteral obstruction (UUO) in mice. UUO-associated fibrosis was suppressed by pharmacological inhibitors of autophagy and also by kidney proximal tubule-specific knockout of autophagy-related 7 (PT-Atg7 KO). Consistently, proliferation and activation of fibroblasts, as indicated by the expression of ACTA2/α-smooth muscle actin and VIM (vimentin), was inhibited in PT-Atg7 KO mice, so was the accumulation of extracellular matrix components including FN1 (fibronectin 1) and collagen fibrils. Tubular atrophy, apoptosis, nephron loss, and interstitial macrophage infiltration were all inhibited in these mice. Moreover, these mice showed a specific suppression of the expression of a profibrotic factor FGF2 (fibroblast growth factor 2). In vitro, TGFB1 (transforming growth factor β 1) induced autophagy, apoptosis, and FN1 accumulation in primary proximal tubular cells. Inhibition of autophagy suppressed FN1 accumulation and apoptosis, while enhancement of autophagy increased TGFB1-induced-cell death. These results suggest that persistent activation of autophagy in kidney proximal tubules promotes renal interstitial fibrosis during UUO. The profibrotic function of autophagy is related to the regulation on tubular cell death, interstitial inflammation, and the production of profibrotic factors.

Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction

Molecular Mechanisms and Therapeutic Targets for Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Renin-angiotensin-aldosterone system (RAAS) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown efficacy in reducing the risk of ESRD. However, patients vary in their response to RAAS blockades, and the pharmacodynamic responses to SGLT2 inhibitors decline with increasing severity of renal impairment. Thus, effective therapy for DKD is yet unmet. Transforming growth factor-β1 (TGF-β1), expressed by nearly all kidney cell types and infiltrating leukocytes and macrophages, is a pleiotropic cytokine involved in angiogenesis, immunomodulation, and extracellular matrix (ECM) formation. An overactive TGF-β1 signaling pathway has been implicated as a critical profibrotic factor in the progression of chronic kidney disease in human DKD. In animal studies, TGF-β1 neutralizing antibodies and TGF-β1 signaling inhibitors were effective in ameliorating renal fibrosis in DKD. Conversely, a clinical study of TGF-β1 neutralizing antibodies failed to demonstrate renal efficacy in DKD. However, overexpression of latent TGF-β1 led to anti-inflammatory and anti-fibrosis effects in non-DKD. This evidence implied that complete blocking of TGF-β1 signaling abolished its multiple physiological functions, which are highly associated with undesirable adverse events. Ideal strategies for DKD therapy would be either specific and selective inhibition of the profibrotic-related TGF-β1 pathway or blocking conversion of latent TGF-β1 to active TGF-β1.

/pdf/transforming-growth-factor-beta1-in-diabetic-kidney-disease-5721avih8d.pdf

Transforming Growth Factor-Beta1 in Diabetic Kidney Disease

Diabetic retinopathy, classified using the lesion-aware deep learning system, predicts diabetic end-stage renal disease in chinese patients.

Background: To investigate the relationship between serum iron status and renal outcome in patients with type 2 diabetes mellitus (T2DM). Methods: Chinese patients (n=111) with T2DM and biopsy-proven diabetic nephropathy (DN) were surveyed in a longitudinal, retrospective study. Serum iron, total iron-binding capacity, ferritin, and transferrin were measured at the time of renal biopsy. Iron deposition and transferrin staining were performed with renal biopsy specimens of DN patients and potential kidney donors. End-stage renal disease (ESRD) was the end-point. ESRD was defined as an estimated glomerular filtration rate <15 mL/min/1.73 m2 or the need for chronic renal replacement therapy. Cox proportional hazard models were used to estimate the hazard ratios (HRs) for the influence of serum iron metabolism on ESRD. Results: During a median follow up of 30.9 months, 66 (59.5%) patients progressed to ESRD. After adjusting for age, sex, baseline systolic blood pressure, renal functions, hemoglobin, HbA1c, and pathological findings, lower serum transferrin concentrations were significantly associated with higher ESRD in multivariate models. Compared with patients in the highest transferrin quartile (≥1.65 g/L), patients in the lowest quartile (≤1.15 g/L) had multivariable-adjusted HR (95% confidence interval) of 7.36 (1.40-38.65) for ESRD. Moreover, tubular epithelial cells in DN exhibited a higher deposition of iron and transferrin expression compared with healthy controls. Conclusions: Low serum transferrin concentration was associated with diabetic ESRD in patients with T2DM. Free iron nephrotoxicity and poor nutritional status with accumulated iron or transferrin deposition might contribute to ESRD.

/pdf/serum-transferrin-predicts-end-stage-renal-disease-in-type-2-5ccu6oe0ie.pdf

Serum transferrin predicts end-stage Renal Disease in Type 2 Diabetes Mellitus patients.

This retrospective study included 299 patients with type 2 diabetes mellitus and biopsy-confirmed diabetic nephropathy (DN) to investigate the prognostic value of alkaline phosphatase (ALP) for ren...

Association between serum alkaline phosphatase and renal outcome in patients with type 2 diabetes mellitus

Chronic kidney disease (CKD) and diabetes mellitus increase atherosclerotic cardiovascular diseases (ASCVD) risk. However, the association between renal outcome of diabetic kidney disease (DKD) and...

/pdf/association-between-atherosclerotic-cardiovascular-diseases-1hvbeym3ii.pdf

Yutong Zou

Papers

Transforming Growth Factor-Beta1 in Diabetic Kidney Disease

Diabetic retinopathy, classified using the lesion-aware deep learning system, predicts diabetic end-stage renal disease in chinese patients.

Serum transferrin predicts end-stage Renal Disease in Type 2 Diabetes Mellitus patients.

Association between serum alkaline phosphatase and renal outcome in patients with type 2 diabetes mellitus

Association between atherosclerotic cardiovascular diseases risk and renal outcome in patients with type 2 diabetes mellitus